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Book Chapter

Chemotherapy - Pharmacology for Medical Graduates, 4th Updated Edition

Shanbhag, Tara V, MD; Shenoy, Smita, MD;

Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 11, 367-469


General considerations PH1.42

Chemotherapy

Chemotherapy is the treatment of infectious diseases or malignancy with drugs which destroy microorganisms or cancer cells preferentially with minimal damage to host tissues. The infection may be due to bacteria, virus, fungi, protozoa or helminths.

Bactericidal agents

They kill or destroy microorganisms, e.g. penicillins, cephalosporins and aminoglycosides.

Bacteriostatic agents

They inhibit the growth and multiplication of microorganisms, e.g. sulphonamides, tetracyclines, chloramphenicol and erythromycin.

At high concentration, some of the ‘static’ drugs may produce ‘cidal’ effect; for example, chloramphenicol is a bacteriostatic drug, but at high concentrations it is bactericidal against Haemophilus influenzae and Neisseria meningitidis .

Antimicrobial agents

Antimicrobial agents (AMAs) are naturally obtained, semisynthetic and synthetic drugs that act against microorganisms. Natural sources include bacteria (bacitracin, colistin, polymyxin B, aztreonam), fungi (penicillin, cephalosporin, griseofulvin) and actinomycetes (tetracyclines, chloramphenicol, aminoglycosides, macrolides).

Antibiotics

Antibiotics are substances obtained from microorganisms that kill or inhibit growth of other microorganisms at a very low concentration.

Minimum inhibitory concentration

Minimum inhibitory concentration (MIC) is the minimum concentration of an AMA that prevents visible growth of a microorganism.

Classification of antimicrobial agents

  • I

    According to their type of action

    • (a)

      Bactericidal agents

      • Penicillins

      • Cephalosporins

      • Aminoglycosides

      • Fluoroquinolones

      • Rifampin

      • Metronidazole

    • (b)

      Bacteriostatic agents

      • Tetracyclines

      • Chloramphenicol

      • Sulphonamides

      • Dapsone

      • Erythromycin

      • Clindamycin

  • II

    According to their spectrum of activity

    • (a)

      Narrow-spectrum antibiotics

      • Penicillin G

      • Aminoglycosides

    • (b)

      Broad-spectrum antibiotics

      • Tetracyclines

      • Chloramphenicol

  • III

    According to their mechanism of action ( Fig. 11.1 )

    • 1.

      Drugs that inhibit cell wall synthesis, e.g. penicillins, cephalosporins, carbapenems, bacitracin, vancomycin, cycloserine

    • 2.

      Drugs that affect cell membrane function, e.g. amphotericin B (AMB), nystatin, polymyxin

    • 3.

      Drugs that inhibit protein synthesis, e.g. chloramphenicol, tetracyclines, erythromycin, linezolid, clindamycin

    • 4.

      Drugs that alter protein synthesis by misreading of mRNA code and premature termination of mRNA translation, e.g. aminoglycosides

    • 5.

      Drugs that inhibit viral DNA synthesis, e.g. acyclovir, ganciclovir, zidovudine

    • 6.

      Drugs that affect DNA function, e.g. rifampin, rifabutin

    • 7.

      Drugs that inhibit DNA gyrase, e.g. fluoroquinolones (FQs)

    • 8.

      Antimetabolites, e.g. sulphonamides, dapsone, trimethoprim, pyrimethamine

    Fig. 11.1
    Classification of antimicrobials based on their mechanism of action. PABA, para -aminobenzoic acid; DHFA, dihydrofolic acid; THFA, tetrahydrofolic acid.

Resistance to antimicrobial agents

It is said to occur when the microorganism does not respond to the AMA which would normally kill or inhibit its growth. The resistance may be natural or acquired . Natural resistance is genetically determined, e.g. normally, gram-negative bacilli are not affected by penicillin G.

In acquired resistance, microbes that initially respond to an AMA develop resistance later to the same AMA by mutation or gene transfer. Mutation is a permanent alteration in the sequence of DNA. Resistance can be single-step mutation (e.g. resistance of Staphylococcus to rifampin) or multistep mutation (mutation in a gene, which results in resistance, occurs in more than one step; the microorganism becomes gradually less sensitive to the drug, e.g. resistance to erythromycin). The transfer of genes for drug resistance occurs by the following mechanisms:

Transduction.

There is transfer of DNA, carrying a gene for resistance, from one bacterium to another through bacteriophage, e.g. resistance of strains of Staphylococcus aureus to antibiotics is mediated via transduction.

Transformation.

The resistance carrying genetic material, which is released into the environment by resistant bacteria, is taken up by other sensitive bacteria which then become resistant to the AMA, e.g. penicillin G resistance in pneumococci.

Conjugation.

Conjugation is the transfer of genetic material carrying resistance between bacteria by direct contact through sex pilus, e.g. Escherichia coli resistance to streptomycin.

Development of resistance to antimicrobial agents.

There are several mechanisms by which an organism can develop resistance to an AMA. The important mechanisms are as follows:

  • 1.

    Production of inactivating enzymes : For example, staphylococci, gonococci and E. coli produce β-lactamases that can destroy some of the penicillins and cephalosporins.

  • 2.

    An efflux pump mechanism : It is a mechanism that prevents the accumulation of the drug in the microorganism, e.g. resistance of gram-positive and gram-negative bacteria to tetracyclines, chloramphenicol, macrolides, etc.

  • 3.

    Decreased entry of AMA into the organism due to alteration in the channel/transporter required for its entry into the organism.

  • 4.

    Alteration of the binding site : For example, change in penicillin-binding proteins (PBPs) in case of certain pneumococci with decreased affinity for penicillins.

  • 5.

    Absence of metabolic pathway : For example, sulphonamide-resistant bacteria can utilize preformed folic acid without the need for usual metabolic steps.

Cross-resistance.

Organisms that develop resistance to an AMA may also show resistance to other chemically related AMAs. The cross-resistance among AMAs could be either one-way or two-way. Cross-resistance among tetracyclines and sulphonamides is usually ‘two-way’.

The ‘one-way’ resistance is seen between neomycin and streptomycin. Neomycin-resistant organisms are resistant to streptomycin but streptomycin-resistant organisms may be sensitive to neomycin.

Prevention of development of resistance to antimicrobial agents.

It is done by:

  • 1.

    Selecting right AMA.

  • 2.

    Giving right dose of the AMA for proper duration.

  • 3.

    Proper combination of AMAs, e.g. in tuberculosis (TB), multidrug therapy (MDT) is used to prevent development of resistance to antitubercular drugs by mycobacteria.

Superinfection (suprainfection)

It is defined as the occurrence of a new infection due to antimicrobial therapy for another infection. The causative organism of superinfection should be different from that of the primary disease. Most of the AMAs – especially broad-spectrum antibiotics (tetracyclines and chloramphenicol), clindamycin, ampicillin, etc. – alter the normal bacterial flora, as a result of which the host-defence mechanism is impaired. Hence, pathogenic organisms invade the host, multiply and produce superinfection. The causative organism may be fungi or bacteria.

Pathogenesis.

Superinfection is associated with suppression/change of normal flora in the body following treatment with certain antimicrobials. The pathogenesis of superinfection is described in Fig. 11.2 .

Fig. 11.2
Pathogenesis of superinfection. (A) Absence of bacteriocins promotes growth of pathogens. (B) Alteration in normal flora favours utilization of nutrients by pathogens.

The sites involved in superinfection are those body cavities that have direct communication with the exterior, i.e. rectum, oral cavity, vagina, lower urinary tract, upper respiratory tract, etc. ( Table 11.1 ).

Table 11.1 ■
Microorganisms causing superinfection and its treatment
Manifestations Microorganisms Treatment
Diarrhoea, oral thrush Candida albicans Nystatin, clotrimazole, fluconazole
Pseudomembranous enterocolitis Clostridium difficile Metronidazole, vancomycin
Urinary tract infection Escherichia coli, Proteus, Pseudomonas Ciprofloxacin, gentamicin, carbenicillin

Factors predisposing to superinfection.

Superinfection is common in immunocompromised conditions, such as diabetes, malignancy and AIDS, and also during prolonged corticosteroid therapy. It can be minimized by (i) using specific AMAs, (ii) avoiding unnecessary use of AMAs and (iii) use of probiotics, e.g. Lactobacillus .

Chemoprophylaxis

Chemoprophylaxis is the administration of AMAs to prevent infection or to prevent development of disease in persons who are already infected (see Table 11.2 ). The ideal time to initiate therapy is before the organism enters the body or at least before the development of signs and symptoms of the disease.

Table 11.2 ■
Chemoprophylactic regimens
Infection Antimicrobial agent with dose and duration
  • 1.

    Meningococcal and Haemophilus influenzae meningitis

  • Rifampin 600 mg orally, every 12 hours for four doses. Children 10 mg/kg orally, every 12 hours for four doses

  • Rifampin is the most effective antimicrobial agent in eradicating the organism from nasopharynx, thus eliminating carrier state

  • 2.

    Rheumatic fever

  • Benzathine penicillin G 1,200,000 units i.m. once a month and continued for lifetime

  • 3.

    Tuberculosis

  • INH (isoniazid) 5 mg/kg orally, daily for 6 months

  • 4.

    Chemoprophylaxis for endocarditis before surgical procedures

    • a Oral regimens

    • If patient is allergic to penicillin

    • a Parenteral regimens

    • If patient is allergic to β-lactams

  • Amoxicillin 2 g, 1 hour before procedure

  • Clindamycin 600 mg, 1 hour before procedure

  • or

  • Azithromycin 500 mg, 1 hour before procedure

  • Ampicillin 2 g i.m. or i.v., 30 minutes before procedure

  • or

  • Cefazolin 1 g i.v. or i.m., 30 minutes before procedure

  • Clindamycin 600 mg i.v., 1 hour before procedure

INH, isonicotinic acid hydrazide.

a These regimens are also used for surgical prophylaxis.

Indications for chemoprophylaxis

  • 1.

    To prevent endocarditis in patients with valvular lesion before undergoing surgical procedures : Surgical procedure → mucosal damage → bacteraemia → affects damaged valve → endocarditis.

  • 2.

    To protect healthy persons : Chloroquine/mefloquine is used for chemoprophylaxis of malaria for those travelling to malaria endemic area.

  • 3.

    To prevent infection in patients undergoing organ transplantation : Oral FQs can be used.

  • 4.

    To prevent opportunistic infections in immunocompromised patients , e.g. cotrimoxazole is used to prevent Pneumocystis jiroveci pneumonia in AIDS patients.

  • 5.

    Prior to surgical procedures : AMAs are administered to all patients prior to major surgical procedures or implantation of prosthetic devices and in diabetic patients or patients on prolonged corticosteroids to prevent wound infection after surgery.

  • 6.

    To prevent infection in patients with burns : Topical silver sulphadiazine and systemic antibiotics are used.

  • 7.

    To prevent infection in patients with urinary catheter : FQs are used in patients who are at high risk of infection.

Suggested chemoprophylactic regimens.

The effectiveness of chemoprophylaxis depends on the selection of a specific AMA, its dosage, time of initiation and duration of antimicrobial therapy. The suggested chemoprophylactic regimens are listed in Table 11.2 .

  • Empirical therapy: It is the use of AMAs before identification of causative organism or availability of susceptibility test results, e.g. combination of cefotaxime, vancomycin and ampicillin is used as empirical therapy for suspected bacterial meningitis (before test results are available) to cover possible organisms likely to cause meningitis.

  • Definitive therapy: It involves the use of AMA after identification/susceptibility tests of the causative organism responsible for the disease.

Combination of antimicrobial agents

It is the simultaneous use of two or more AMAs for the treatment of certain infectious diseases.

Indications/advantages of antimicrobial combinations

  • 1.

    To broaden the spectrum of activity in mixed bacterial infections : Intra-abdominal, pulmonary, hepatic, pelvic, brain abscesses, etc., are often due to both aerobic and anaerobic organisms. Hence, they require antimicrobial combination therapy.

    • Metronidazole + ceftriaxone for brain abscess

  • 2.

    To broaden the spectrum of action in severe infections when the aetiology is not known : Combination of cefotaxime, vancomycin and ampicillin is used for empirical therapy of suspected bacterial meningitis. Later, the AMA should be selected according to the type of organism, culture and sensitivity results.

  • 3.

    To increase antibacterial activity in the treatment of specific infections (for synergistic effect)

    • Ampicillin (bactericidal) + gentamicin (bactericidal) for enterococcal endocarditis

    • Carbenicillin + gentamicin for infections due to Pseudomonas

      • Penicillins, by inhibiting bacterial cell wall synthesis, facilitate the entry of gentamicin into the bacterial cell (synergistic effect) resulting in more complete eradication of the organism.

    • Sulphamethoxazole + trimethoprim for Pneumocystis jiroveci pneumonia (see p. 377 for mechanism of action)

    • Rifampin (cidal) + dapsone (static) in leprosy – synergistic effect

  • 4.

    To prevent emergence of resistant microorganisms : In TB, leprosy and HIV infection, combination therapy is used.

  • 5.

    To reduce duration of therapy : MDT is used in TB and leprosy.

  • 6.

    To reduce adverse effects : AMB and flucytosine in cryptococcal meningitis: The dose-dependent toxicity (especially nephrotoxicity) of AMB is decreased due to reduction in dosage (see p. 425).

Disadvantages of antimicrobial drug combinations

  • 1.

    Increased toxicity , e.g. vancomycin with tobramycin may cause enhanced nephrotoxicity.

  • 2.

    Increased cost .

  • 3.

    Decreased antibacterial activity due to improper combinations, e.g. in pneumococcal meningitis, activity of penicillin G (bactericidal) against pneumococci will decrease if combined with tetracycline (bacteriostatic). Penicillins act mainly on rapidly multiplying bacteria; tetracycline inhibits multiplication of bacteria because of its static effect, thus reducing effect of penicillins.

  • 4.

    Increased likelihood of superinfection .

  • 5.

    Irrational combination of AMAs can lead to development of resistance .

List of microorganisms

  • 1.

    Gram-positive cocci: S. aureus , Streptococcus pyogenes , Streptococcus viridans , Streptococcus β-haemolyticus , S. pneumoniae (pneumococcus), Enterococcus

  • 2.

    Gram-negative cocci: Neisseria gonorrhoeae , N. meningitidis

  • 3.

    Gram-positive bacilli: Bacillus anthracis , Corynebacterium diphtheriae , Clostridium tetani , Clostridium perfringens , Clostridium difficile

  • 4.

    Gram-negative bacilli: E. coli , Enterobacter spp., Proteus , Pseudomonas , Salmonella , Shigella , H. influenzae , H. ducreyi , Klebsiella , Brucella , Vibrio cholerae

  • 5.

    Acid-fast bacilli: Mycobacterium tuberculosis , Mycobacterium leprae , Mycobacterium avium complex (MAC)

  • 6.

    Spirochetes: Treponema pallidum , Leptospira

  • 7.

    Others: Rickettsia , Mycoplasma pneumoniae , Chlamydia trachomatis , Helicobacter pylori , etc.

Selection of an appropriate antimicrobial agent ( fig. 11.3 )

Patient factors

  • 1.

    Age: Use of chloramphenicol in premature infants may produce grey baby syndrome because metabolic functions of liver and renal excretion are not fully developed. Sulphonamides in neonates can cause kernicterus.

    • Renal function declines with age; hence, elderly patients are more prone to ototoxicity and nephrotoxicity with aminoglycosides due to their reduced clearance by kidney.

  • 2.

    History of allergy: In patients with history of asthma, allergic rhinitis, hay fever, etc., there is an increased risk of penicillin allergy; hence, such drugs should be avoided in them.

  • 3.

    Genetic abnormalities: Primaquine, pyrimethamine, sulphonamides, sulphones, FQs, etc., may cause haemolysis in patients with G6PD deficiency.

  • 4.

    Pregnancy: Most of the AMAs cross placental barrier and may affect the developing fetus. The risk of teratogenicity is highest during the first trimester. For example, use of tetracyclines during pregnancy may affect fetal dentition and bone growth. There is an increased incidence of hepatotoxicity with tetracycline in pregnant women.

  • 5.

    Host defences: In immunocompromised patients (AIDS, leukaemias and other malignancies), normal defence mechanisms are impaired – bacteriostatic drugs may not be adequate; hence bactericidal agents should be used to treat infection.

  • 6.

    Hepatic dysfunction: In patients with hepatic dysfunction, drugs like chloramphenicol, erythromycin and rifampin should be avoided or require dose reduction to minimize toxic effects.

  • 7.

    Renal dysfunction: In renal failure, drugs that are eliminated via kidney can accumulate in the body and cause severe toxic effects. Hence, aminoglycosides, vancomycin, AMB, FQs, etc., should be avoided or require dose reduction in patients with impaired renal function.

  • 8.

    Local factors

    • (a)

      Antimicrobial activity of sulphonamides is markedly reduced in the presence of pus.

    • (b)

      The activity of aminoglycosides is enhanced at alkaline pH.

Fig. 11.3
Factors affecting selection of an antimicrobial agent.

Drug factors

  • 1.

    Route of administration: Depending on the severity and site of infection, AMAs have to be chosen. Some of the AMAs can be administered orally as well as parenterally. For mild-to-moderate infections, oral route is usually preferred, but for severe infections like endocarditis and meningitis, parenteral AMAs are preferred during initial stages of therapy. Some AMAs like aminoglycosides are not effective orally; they are administered parenterally for systemic infections.

  • 2.

    The spectrum of antimicrobial activity: It is an important factor while selecting an AMA especially during empirical therapy.

  • 3.

    Bactericidal/bacteriostatic effect: Bactericidal drugs kill organisms, while static drugs inhibit growth and multiplication. In immunocompromised states, the host-defence mechanisms are impaired; hence, bactericidal drugs are required even for trivial infections.

  • 4.

    Cost of AMA: The cost of treatment has to be considered while selecting an AMA. The expensive antimicrobials should not be used routinely when alternative cheaper and effective AMAs are available.

  • 5.

    Pharmacokinetic/pharmacodynamic considerations

    • Time-dependent inhibition: This is observed with certain AMAs like β-lactams and glycopeptides. Their antimicrobial action depends on the duration of time the drug concentration remains above the MIC in the dosing interval. Thus, they are administered in multiple doses.

    • Concentration-dependent killing: For aminoglycosides and FQs, the antimicrobial effect depends on the ratio of peak plasma concentration to MIC. A single daily dose of aminoglycosides is as/more effective than multiple doses.

    • Ability to penetrate into the infected area

      • Ability to cross the blood–brain barrier (BBB): Clindamycin is effective against anaerobes, but not useful for anaerobic brain abscess as it does not reach cerebrospinal fluid (CSF) and brain. Anaerobic brain abscess can be treated effectively with third-generation cephalosporins or combination of metronidazole and chloramphenicol.

      • Levofloxacin attains good concentration in the lung, skin/soft tissues and urinary tract – produces high cure rates in community-acquired pneumonia, skin infections, etc.

Organism-related factors.

In severe infections, empirical therapy with antimicrobial drug combination should be initiated depending on the clinical diagnosis. Later, the AMA should be selected according to the type of organism, culture and sensitivity reports. The bacterial resistance to AMAs and cross-resistance should also be considered while selecting an AMA.

Sulphonamides

Sulphonamides were the first effective AMAs used in the treatment of bacterial infections in humans. They are derivatives of sulphanilamide ( para -aminobenzene sulphonamide) and are synthetic compounds ( Fig. 11.4 ).

Fig. 11.4
Basic structure of sulphonamides.

Mechanism of action.

para -Aminobenzoic acid (PABA) is a precursor of folic acid which is essential for growth and multiplication of many bacteria. Sulphonamides, being structurally similar to PABA, competitively inhibit folate synthase enzyme and prevent the formation of folic acid, thereby producing bacteriostatic effect. They are not effective in the presence of pus as it is rich in PABA, purines and thymidine. Mammalian cells do not synthesize folic acid, but utilize folic acid present in diet, hence are unaffected by sulphonamides.

Bacterial resistance to sulphonamides.

Most of the bacteria have developed resistance to sulphonamides. It could be due to:

  • 1.

    Decreased affinity of folate synthetase for the drug

  • 2.

    Efflux of the drug by bacteria

  • 3.

    Development of alternate metabolic pathway for folate synthesis

Pharmacokinetics.

All systemic-acting sulphonamides are well absorbed from the gut. They are bound to plasma proteins, particularly albumin. Sulphonamides are distributed in almost all tissues of the body including CSF. They cross placental barrier and reach fetal circulation; they are metabolized in liver mainly by acetylation. The acetylated products have no antibacterial activity but retain the toxic potential of the parent compound. Sulphonamides are excreted partly unchanged and partly as metabolic products.

Adverse effects

  • 1.

    The acetylated products of sulphonamides are poorly soluble in acidic urine and may cause crystalluria, haematuria or even obstruction to urinary tract. This may be avoided by taking plenty of water and alkalinizing the urine.

  • 2.

    Hypersensitivity reactions include skin rashes, itching, drug fever and exfoliative dermatitis. Stevens–Johnson syndrome is the most severe type of hypersensitivity reaction characterized by fever, erythema multiforme and ulceration of mucous membranes.

  • 3.

    In patients with glucose-6-phosphate dehydrogenase deficiency, sulphonamides may cause acute haemolytic anaemia.

  • 4.

    Rarely cause hepatitis and suppression of bone marrow.

  • 5.

    Use of sulphonamides in neonates, especially in premature babies, may cause displacement of bilirubin from plasma proteins. The free bilirubin can cross BBB and get deposited in the basal ganglia resulting in kernicterus.

Drug interactions.

Sulphonamides potentiate the effect of phenytoin, methotrexate (MTX), oral anticoagulants and oral hypoglycaemic agents (sulfonylureas) by inhibiting their metabolism and displacing them from plasma protein binding sites.

Therapeutic uses.

Sulphonamides alone are rarely used now for systemic infections. They are used in combination with other AMAs.

  • 1.

    Sulphadoxine and pyrimethamine are used in combination with artesunate in the treatment of chloroquine-resistant Plasmodium falciparum malaria.

  • 2.

    Sulphadiazine and pyrimethamine combination is the drug of choice for toxoplasmosis.

  • 3.

    Nocardiosis: Sulphamethoxazole in combination with trimethoprim is used.

  • 4.

    Sulphamethoxazole in combination with trimethoprim is used in the treatment of P. jiroveci infection in patients with AIDS.

  • 5.

    Sodium salt of sulphacetamide is used exclusively for the treatment of ophthalmic infections. It is administered as eye drops or eye ointment. It is preferred because of:

    • (a)

      High aqueous solubility

    • (b)

      Neutral pH and nonirritant nature of the drug

    • (c)

      Good penetrability on topical administration

    • (d)

      Low incidence of hypersensitivity reactions

    • (e)

      Low cost

  • 6.

    Silver sulfadiazine and mafenide are used topically for preventing infection of burn wound. Silver sulfadiazine slowly releases silver ions which are toxic to microorganisms. It is not effective in the presence of pus and tissue fluid.

  • 7.

    Sulphasalazine is useful in the treatment of inflammatory bowel disease and rheumatoid arthritis.

  • 8.

    Rheumatic fever: Sulphadiazine can be used for prophylaxis of rheumatic fever.

Cotrimoxazole

Cotrimoxazole is a World Health Organization (WHO)–approved fixed-dose combination of sulphamethoxazole and trimethoprim in the ratio of 5:1. It was introduced in late 1960s; even today, it is one of the commonly used AMAs.

Mechanism of action

Cotrimoxazole (sulphamethoxazole and trimethoprim in a dose ratio of 5:1) produces sequential blockade , i.e. two drugs interfere with two successive steps in the same metabolic pathway; hence, their combination produces supra-additive effect. Sulphamethoxazole inhibits folate synthetase, whereas trimethoprim inhibits folate reductase enzyme. The pharmacokinetic properties of these two drugs match each other almost closely, hence are selected for combination. They have similar half-lives. Optimum synergistic effect is seen at a concentration ratio of 20:1 (sulphamethoxazole to trimethoprim) in blood and tissues. The advantages of this combination are the following:

  • 1.

    Individually, both are bacteriostatic but the combination has cidal effect.

  • 2.

    Chances of development of bacterial resistance is greatly reduced.

Pharmacokinetics.

Cotrimoxazole is well absorbed after oral administration and is also available for parenteral use, widely distributed to various tissues including CSF and sputum, metabolized in liver and excreted mainly in urine; hence, dose reduction is needed in patients with renal insufficiency.

Adverse effects.

Cotrimoxazole is well tolerated in most patients. Most of the adverse effects are same as those of sulphonamides. The common adverse effects are skin rashes and gastrointestinal (GI) disturbances. Exfoliative dermatitis, erythema multiforme and Stevens–Johnson syndrome are rare. GI symptoms include nausea, vomiting, glossitis and stomatitis. Megaloblastic anaemia due to folate deficiency may occur rarely, especially in alcoholics and malnourished persons. Bone marrow suppression with leucopenia, neutropenia and thrombocytopenia occurs rarely. Cotrimoxazole is contraindicated in pregnancy.

The preparations of cotrimoxazole are shown in Table 11.3 .

Table 11.3 ■
Preparations of cotrimoxazole
Strength of cotrimoxazole Preparations
Sulphamethoxazole 400 mg + trimethoprim 80 mg Oral, i.v.
Sulphamethoxazole 800 mg + trimethoprim 160 mg Double strength (DS); oral, i.m.
Sulphamethoxazole 200 mg + trimethoprim 40 mg Oral suspension
Sulphamethoxazole 100 mg + trimethoprim 20 mg Paediatric tablet

Therapeutic uses

  • 1.

    Urinary tract infection (UTI): Cotrimoxazole is effective for the treatment of acute uncomplicated lower UTIs due to gram-negative organisms such as E. coli , Proteus and Enterobacter spp. The usual dose is 800 mg sulphamethoxazole plus 160 mg of trimethoprim (cotrimoxazole double-strength tablet) b.d. for 3 days. It is useful for chronic and recurrent lower UTIs especially in women. Small doses of cotrimoxazole daily or thrice weekly are used for long-term prophylaxis in recurrent UTI. Cotrimoxazole can be used in the treatment of bacterial prostatitis as it is concentrated in prostatic tissue.

  • 2.

    Respiratory tract infections: Cotrimoxazole is useful for acute and chronic bronchitis due to H. influenzae and Moraxella catarrhalis . It is also useful for acute maxillary sinusitis and otitis media.

  • 3.

    Bacterial diarrhoeas: Cotrimoxazole may be used for GI infections due to Shigella , E. coli and Salmonella spp. But FQs are the preferred agents.

  • 4.

    Pneumocystis jiroveci infection: High doses of cotrimoxazole are used for treatment of infection due to P . jiroveci in immunocompromised patients. It is useful for treatment as well as prophylaxis of P . jiroveci pneumonia. Pentamidine, clindamycin, primaquine and atovaquone are the alternative drugs for P . jiroveci infection.

  • 5.

    Nocardiosis: Cotrimoxazole has been used in the treatment of infection due to Nocardia spp.

  • 6.

    Chancroid: It is caused by H. ducreyi . The drug of choice is azithromycin. Cotrimoxazole is equally effective. The alternative drugs are ceftriaxone and ciprofloxacin.

  • 7.

    Typhoid fever (see p. 382): Fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third-generation cephalosporins (ceftriaxone and cefoperazone) are the treatment of choice for typhoid fever. Cotrimoxazole may also be effective.

Quinolones and fluoroquinolones

The first quinolone, nalidixic acid, is a urinary antiseptic. It is effective against gram-negative bacteria including E. coli , Proteus , Klebsiella , Enterobacter , Salmonella and Shigella , but not Pseudomonas . Nalidixic acid inhibits DNA gyrase enzyme and interferes with the replication of bacterial DNA. It is useful in the treatment of uncomplicated UTI due to gram-negative bacteria and diarrhoea due to Shigella or Salmonella . The most common adverse effects are related to the GI tract, central nervous system (CNS) and skin.

Fluoroquinolones (FQs) are synthetic, fluorinated analogues of nalidixic acid. The important FQs are norfloxacin, ciprofloxacin, pefloxacin (first-generation FQs), ofloxacin, levofloxacin, gemifloxacin and moxifloxacin (second-generation FQs) ( Table 11.4 ).

Table 11.4 ■
Pharmacokinetics, antibacterial spectrum, uses and drug interactions of fluoroquinolones
Fluoroquinolone Routes of administration Oral bioavailability Elimination t ½ (hours) Antibacterial spectrum and uses Drug interactions
First generation
Norfloxacin
Oral, topical (eye) 30%–40% 4–6 Mainly against gram-negative organisms, but not Pseudomonas
Uses: It is used mainly in the treatment of urinary tract infection and bacterial diarrhoeas due to Escherichia coli, Shigella, Salmonella , etc.
Inhibits metabolism of theophylline and warfarin
Ciprofloxacin Oral, i.v. infusion, topical (eye drops, ointment) 70% 3–5 See pp. 379, 382 Inhibits metabolism of theophylline and warfarin
Pefloxacin Oral, i.v. infusion Almost 100% 7–14 Similar to ciprofloxacin, also effective against Mycobacterium leprae
Uses: Typhoid, gonococcal infections, meningitis due to gram-negative organisms, UTI and bacterial diarrhoeas
Inhibits metabolism of theophylline and warfarin
Ofloxacin Oral, i.v. infusion, topical (eye drops) Almost 100% 4–7 Effective against gram-negative organisms. More active than ciprofloxacin against gram-positive organisms, Chlamydia, Mycoplasma and mycobacteria
Uses: Tuberculosis (TB), leprosy, atypical pneumonia and bacterial conjunctivitis
Inhibits metabolism of theophylline but to a lesser extent
Second generation
Levofloxacin
Oral, i.v., topical (eye drops) 100% 8 Increased activity against Streptococcus pneumoniae , effective against gram-negative bacteria and anaerobes
Uses: Community-acquired pneumonia, chronic bronchitis, typhoid, bacterial conjunctivitis, skin, soft-tissue and urinary tract infection
No interaction with theophylline and warfarin
Gemifloxacin Oral 70% 8–10 Effective against S. pneumoniae and some anaerobes
Uses: Community-acquired pneumonia, chronic bronchitis, sinusitis, otitis media and bacterial conjunctivitis
Moxifloxacin Oral, i.v. infusion, topical (eye drops) 90% 12 More active against gram-positive bacteria including S. pneumoniae , M. tuberculosis and some anaerobes ( Bacteroides fragilis )Uses: Community-acquired pneumonia, chronic bronchitis, sinusitis, otitis media and bacterial conjunctivitis
Prulifloxacin (prodrug) Oral; converted to ulifloxacin (active) Well absorbed Effective against gram-positive and gram-negative organisms
Uses: It is used mainly in the treatment of urinary tract infection and bronchitis
UTI, urinary tract infection.

Mechanism of action

FQs inhibit bacterial DNA synthesis (bactericidal). They inhibit DNA gyrase, thus blocking DNA replication in gram-negative bacteria. Inhibition of topoisomerase IV in gram-positive bacteria prevents separation of replicated DNA.

Antibacterial spectrum

Ciprofloxacin is the prototype drug. It is highly effective against aerobic gram-negative organisms – E. coli , Enterobacter , Proteus , Klebsiella , Salmonella , Shigella , H. ducreyi , H. influenzae , N. gonorrhoeae , N. meningitidis , V. cholerae and Campylobacter jejuni .

It has activity against S. aureus , Pseudomonas aeruginosa and M. tuberculosis .

Most of the anaerobes, Bacteroides fragilis , C. difficile , etc. are resistant to ciprofloxacin.

Newer FQs like levofloxacin, gemifloxacin and moxifloxacin have greater activity against streptococci and some activity against anaerobes.

Pharmacokinetics.

Ciprofloxacin is administered by oral, i.v. or topical routes. It is well absorbed from the gut, but food delays its absorption. It is widely distributed in the body, and reaches high concentration in kidney, lung, prostatic tissue, bile, macrophages, etc. It is excreted mainly in urine.

Adverse effects

  • The common adverse effects are related to the GI tract, e.g. nausea, vomiting and abdominal discomfort.

  • CNS effects include headache, dizziness, insomnia, confusion, hallucinations and convulsions.

  • Hypersensitivity reactions include skin rashes, urticaria, itching, eosinophilia and photosensitivity.

  • Tenosynovitis and tendon rupture can occur especially in athletes.

  • Moxifloxacin can cause prolongation of QT interval.

  • FQs are contraindicated in pregnancy.

  • FQs have caused cartilage damage in immature animals – hence, they should be avoided in young children.

Drug Interactions. Ciprofloxacin increases the plasma concentration of theophylline, warfarin, etc., by inhibiting their metabolism. Nonsteroidal anti-inflammatory drugs (NSAIDs) may potentiate CNS side effects of FQs – confusion, irritability and rarely convulsions may occur. Like tetracyclines, absorption of FQs is reduced by antacids, ferrous salts and sucralfate.

Other FQs have been discussed in Table 11.4 .

Balofloxacin (oral) and pazufloxacin (i.v. infusion) are effective against both gram-positive and gram-negative organisms including methicillin-resistant S. aureus (MRSA). They are used in nosocomial infections.

Uses of fluoroquinolones

  • 1.

    UTI: FQs are one of the most commonly used AMAs for UTI. They are effective against gram-negative bacilli, such as E. coli , Proteus and Enterobacter . They also have moderate activity against Pseudomonas infection. FQs are superior to cotrimoxazole for the treatment of UTI. They are also effective for the treatment of bacterial prostatitis as they are concentrated in the prostatic tissue (ciprofloxacin 750 mg b.d. for 3 weeks for upper UTI).

  • 2.

    Prostatitis: FQs are used in prostatitis as an alternative to cotrimoxazole.

  • 3.

    Bacterial diarrhoeas: FQs are effective for a variety of GI infections caused by E. coli , Shigella , Salmonella , etc. For traveller’s diarrhoea (due to E. coli ), FQs are as effective as cotrimoxazole. Norfloxacin, ciprofloxacin or levofloxacin therapy for 3–5 days is adequate.

  • 4.

    Typhoid fever: Ciprofloxacin (750 mg orally b.d. for 10 days) is the preferred drug for treatment of typhoid. It is bactericidal and causes rapid resolution of symptoms. Levofloxacin or ofloxacin can also be used. They are also effective in eliminating chronic carrier state of Salmonella typhi when therapy is continued for 4 weeks as they attain effective concentration in bile and intestinal mucosa. Multidrug-resistant (MDR) cases are treated with ceftriaxone (2 g i.v. for 7 days) or azithromycin (500 mg orally daily for 7 days).

  • 5.

    Sexually transmitted diseases

    • Gonococcal infections : FQs were effective for the treatment of cervicitis and urethritis caused by N. gonorrhoeae but their use has declined because of high rates of resistance.

    • Chancroid: Ciprofloxacin in a dose of 500 mg b.d. for 3 days is effective.

    • Chlamydial cervicitis and urethritis can be treated with levofloxacin or ofloxacin.

  • 6.

    Skin, soft-tissue and bone infections due to S. aureus and gram-negative bacilli require prolonged antimicrobial therapy. FQs can be used in combination with an agent effective against anaerobes especially in diabetic foot infections.

  • 7.

    Ciprofloxacin can be used to eradicate meningococci from nasopharynx, thus eliminating the carrier state, but the preferred drug is rifampin.

  • 8.

    Mycobacterial infections: In MDR-TB, atypical mycobacterial infections, MAC infection in AIDS patients and leprosy, FQs are used in combination with other AMAs.

  • 9.

    Prophylaxis and treatment of infections in neutropenic patients: FQs can be used.

  • 10.

    Ciprofloxacin, levofloxacin, moxifloxacin and ofloxacin are used topically for conjunctivitis due to susceptible organisms.

  • 11.

    Respiratory infections: Newer FQs (levofloxacin and moxifloxacin) are highly effective for community-acquired pneumonia and chronic bronchitis.

  • 12.

    Anthrax: Ciprofloxacin is the preferred drug for treatment and prophylaxis of anthrax.

β-Lactam antibiotics

β-Lactam antibiotics include penicillins, cephalosporins, carbapenems and monobactams. All of them have a β-lactam ring in their chemical structure ( Fig. 11.5 ), hence the name β-lactam antibiotics.

Fig. 11.5
Structure of penicillins.

Penicillins

Penicillin was the first antibiotic developed and used clinically. It was discovered accidentally by Alexander Fleming. The source of penicillin is the high-yielding Penicillium chrysogenum .

Mechanism of action ( fig. 11.6 ).

β-Lactam antibiotics produce bactericidal effect by inhibiting cell wall synthesis in susceptible bacteria.

Fig. 11.6
Cross-linking of peptidoglycan residues and site of action of β-lactam antibiotics.
(Source: Adapted from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th ed) .

Bacterial cell wall is composed of peptidoglycan which contains amino sugars, N -acetylmuramic acid (NAM) and N -acetylglucosamine (NAG). The enzyme, transpeptidase (a PBP), removes terminal alanine of one strand resulting in its linkage with glycine of adjacent strand. Cross-linking makes the cell wall rigid and stable.

β-Lactams, the structural analogues of d-alanine, inhibit transpeptidase, thus inhibiting cross-linking of peptidoglycans and cell wall synthesis. Cell wall–deficient forms are produced which undergo lysis (bactericidal action). β-Lactams exert their cidal effect when the bacteria are actively multiplying and synthesizing cell wall.

PBPs, consisting of transpeptidase, other enzymes and related proteins, are located in the cell membrane of bacteria. The cell wall in gram-positive bacteria is composed mainly of highly cross-linked peptidoglycan, which is 50–100 layers thick and is near the cell surface. In gram-negative bacteria, the peptidoglycan layer is only one to two molecules thick. In addition, there is an outer lipopolysaccharide layer. Hence, gram-negative organisms are less susceptible to penicillin than gram-positive organisms.

Mechanism of bacterial resistance to penicillins.

Bacteria develop resistance (i) by producing β-lactamases, which destroy the β-lactam ring, e.g. S. aureus , E. coli , gonococci and H. influenzae , (ii) due to altered PBPs which have less affinity for β-lactams, e.g. S. pneumoniae , and (iii) due to decreased ability of the drug to penetrate to its site of action.

Pharmacokinetics.

Most of the orally administered penicillin G is destroyed by gastric acid (acid labile); hence, penicillin G is usually given by i.v. route. It can also be administered by i.m. route but is painful. Penicillin G is widely distributed in body tissues, but poorly crosses BBB, although during meningitis, adequate amount reaches the CSF. Penicillin G is rapidly excreted in urine mainly by active tubular secretion. Since renal function is not completely developed in infants and neonates, excretion of penicillins is slow. The action of penicillins can be augmented and prolonged by giving probenecid simultaneously.

Preparations of penicillin G.

The duration of action of penicillin G is increased by combining it with poorly water-soluble compounds, such as procaine (procaine penicillin G) or benzathine (benzathine penicillin G) to yield aqueous suspensions. They are called repository or depot penicillins ( Table 11.5 and Fig. 11.7 ).

Table 11.5 ■
Characteristic features of preparations of penicillin G
Penicillin Route and dose Duration of action Special features
  • 1.

    Penicillin G (benzyl penicillin, crystalline penicillin)

  • i.v., i.m.

  • 20–24 million units (MU) daily

  • 4–6 hours

  • Rapid onset of action, reaches high plasma concentration; mainly used in severe infections – meningitis, endocarditis, pneumonia, etc.

  • 2.

    Repository penicillins (depot penicillins)

  • Procaine penicillin G

  • 600,000–1,200,000 units (0.6–1.2 MU) i.m. daily

  • 12–24 hours

  • Moderate plasma concentration, used in mild-to-moderate infections; less painful because of procaine component

  • Benzathine penicillin G

  • 600,000–2,400,000 units (0.6–2.4 MU), i.m. once a month

  • 3–4 weeks

  • Slow onset but has longest duration of action among penicillins. Used in syphilis, rheumatic fever prophylaxis, etc.

  • Fortified procaine penicillin G

  • 300,000 units procaine penicillin G + 100,000 units penicillin G i.m.

  • 12–24 hours

  • Rapid onset with high plasma concentration and longer duration of action; used in mild-to-moderate infections by sensitive organisms

Fig. 11.7
Preparations of penicillin G with their duration of action and plasma concentration.

Adverse reactions.

Penicillins are relatively safe. They may cause hypersensitivity reactions, such as skin rashes, urticaria, fever, dermatitis, bronchospasm, angioedema, joint pain, serum sickness or anaphylactic reaction.

The major manifestations of anaphylactic shock are severe hypotension, bronchospasm and laryngeal oedema. It is an immunoglobulin E (IgE)–mediated, immediate type of hypersensitivity reaction (type I hypersensitivity). It is not a dose-related adverse drug reaction and can occur with any dosage form of penicillin. Cross-reactivity can occur among penicillins and also among β-lactam antibiotics.

Treatment of anaphylactic shock

  • 1.

    Inj. adrenaline 0.3–0.5 mL of 1:1000 solution intramuscularly

  • 2.

    Inj. hydrocortisone 200 mg intravenously

  • 3.

    Inj. diphenhydramine 50–100 mg intravenously or intramuscularly

Precautions

  • 1.

    Before giving penicillin, history of previous administration and allergic manifestations, if any, must be noted.

  • 2.

    In patients with history of asthma, allergic rhinitis, hay fever, etc., there is an increased risk of penicillin allergy; hence, it should be avoided in such cases.

  • 3.

    Sensitivity test should be performed by an intradermal test on the ventral aspect of forearm. Itching, erythema and wheal formation are watched for. A negative skin test does not ensure absolute safety.

  • 4.

    Inj. adrenaline and hydrocortisone should be kept ready before injecting penicillin to treat the anaphylactic reaction.

Other adverse effects of penicillins are pain and sterile abscess at the site of i.m. injection. Prolonged use of i.v. penicillin G may cause thrombophlebitis.

Jarisch–herxheimer reaction.

It is an acute exacerbation of signs and symptoms of syphilis during penicillin therapy due to release of endotoxins from the dead organisms. The manifestations are fever, chills, myalgia, hypotension, circulatory collapse, etc. It is treated with aspirin and corticosteroids.

Therapeutic uses.

Owing to the risk of anaphylaxis as well as availability of better AMAs, the use of penicillin G has declined. For uses of PnG, see pp. 387 to 389.

Limitations/drawbacks of penicillin G

  • 1.

    Acid labile – orally not very effective

  • 2.

    Short duration of action (to overcome this, repository penicillins have been developed)

  • 3.

    Narrow spectrum of antibacterial activity (mainly against gram-positive organisms)

  • 4.

    Destroyed by penicillinase enzyme

  • 5.

    Possibility of anaphylaxis

To overcome most of the above drawbacks, semisynthetic penicillins have been developed.

Semisynthetic penicillins

The spectrum of action of semisynthetic penicillins, their route of administration and susceptibility to penicillinase is shown in Table 11.6 .

Table 11.6 ■
Classification of penicillins with their spectrum of activity
Penicillins Route of administration Penicillinase susceptible/resistant Antimicrobial spectrum/uses
  • 1.

    Natural penicillins

    • (a)

      Penicillin G

    • (b)

      Procaine penicillin G

    • (c)

      Benzathine penicillin G

  • i.v., i.m.

  • i.m.

  • i.m.

  • Susceptible

  • Streptococcus pyogenes , S. viridans , N. meningitidis , B. anthracis , Corynebacterium diphtheriae , Clostridium spp., spirochetes ( Treponema , Leptospira ), Actinomyces and most of the anaerobes (not Bacteroides fragilis )

  • 2.

    Semisynthetic penicillins

    • (a)

      Acid-resistant penicillin

      • Phenoxymethyl penicillin (penicillin V)

  • Oral

  • Susceptible

  • Similar to penicillin G, attains very low plasma concentration, hence used only for mild streptococcal and pneumococcal infections, trench mouth

  • (b)

    Penicillinase-resistant penicillins

    • Methicillin

    • Oxacillin

    • Cloxacillin

    • Dicloxacillin

  • i.m., i.v.

  • Oral, i.m., i.v.

  • Resistant

  • Sensitive strains of Staphylococcus aureus and S. epidermidis infections (abscesses, cellulitis, pneumonia, etc.)

  • (c)

    Extended-spectrum penicillins

    • Aminopenicillins

    • Ampicillin

    • Amoxicillin

  • Oral, i.m., i.v.

  • Susceptible

  • Antimicrobial spectrum extended to gram-negative bacilli; Escherichia coli , Proteus , Salmonella , Shigella , Haemophilus influenzae and Helicobacter pylori . Of all the oral β-lactams, amoxicillin is the most active agent against both penicillin-sensitive and penicillin-resistant Streptococcus pneumoniae . Ampicillin is highly effective against Listeria monocytogenes

  • Carboxypenicillins Carbenicillin

  • Carbenicillin indanyl

  • Ticarcillin

  • i.m., i.v.

  • Oral

  • i.v.

  • Susceptible

  • Infections caused by Pseudomonas aeruginosa and Proteus spp.

  • Ureidopenicillins

  • Mezlocillin

  • Piperacillin

  • i.m., i.v.

  • i.m., i.v.

  • Susceptible

  • P. aeruginosa , Klebsiella and Enterobacteriaceae infections (pneumonias, burns and UTIs)

UTI, urinary tract infection.

Aminopenicillins

Uses of aminopenicillins

(see pp. 387 to 389)

Adverse effects of aminopenicillins.

The adverse effects of ampicillin are similar to those of penicillin G but skin rashes and diarrhoea are more common.

Carboxypenicillins and ureidopenicillins

They are carbenicillin, carbenicillin indanyl, ticarcillin (carboxypenicillins), mezlocillin and piperacillin (ureidopenicillins).

Uses (see p. 389)

Adverse effects.

They are similar to those of penicillin G. Congestive cardiac failure may be precipitated due to sodium content of carbenicillin sodium. It can also interfere with platelet function and cause bleeding.

Therapeutic uses of penicillins

  • 1.

    Streptoccocal Infections. Ampicillin and amoxicillin ( Table 11.7 ) are effective for pharyngitis, sinusitis, otitis media, bronchitis, etc., caused by S. pyogenes , S. pneumoniae and H. influenzae . Among oral β-lactams, amoxicillin is the most effective agent against penicillin-sensitive and penicillin-resistant S. pneumoniae .

    Table 11.7 ■
    Comparison between ampicillin and amoxicillin
    Ampicillin Amoxicillin
    Semisynthetic, aminopenicillin Semisynthetic, aminopenicillin
    Acid stable; incompletely absorbed from the GI tract – alters intestinal flora; hence, diarrhoea is more common (superinfection) Acid stable, completely absorbed from the GI tract; hence, the incidence of diarrhoea is less
    Food decreases the absorption of ampicillin Food does not decrease the absorption of amoxicillin
    Effective against Shigella and H. influenzae Less effective against Shigella and H. influenzae
    Ampicillin reduces the effectiveness of oral contraceptives Does not reduce the effectiveness of oral contraceptives
    Dose: Ampicillin 250–500 mg q.i.d. Dose: Amoxicillin 250–500 mg t.i.d.
    GI, gastrointestinal.

Rheumatic fever.

The causative organism is group A β-haemolytic Streptococcus . Procaine penicillin G 600,000 units i.m., once daily for 10 days, or benzathine penicillin G 1,200,000 units i.m. as a single dose is used for the treatment of rheumatic fever. For rheumatic fever prophylaxis, inj. benzathine penicillin G is the ideal agent. It is given in a dose of 1.2 million units i.m., once a month and continued for lifetime in high-risk people. Patients allergic to penicillin are treated with erythromycin or sulphadiazine.

  • Subacute bacterial endocarditis (SABE): Ampicillin in combination with gentamicin has been used for the treatment of SABE. Amoxicillin is the most commonly used AMA for prophylaxis of bacterial endocarditis.

  • 2.

    Urinary tract infection (UTI): Fluoroquinolones are the preferred AMAs for UTIs. Ampicillin + gentamicin is useful in E. coli pyelonephritis.

  • 3.

    Meningitis: At present, third-generation cephalosporins along with vancomycin are the drugs of choice for treatment of meningitis caused by S. pneumoniae or N. meningitidis , as the organisms have developed resistance to ampicillin. But ampicillin is very effective for meningitis due to Listeria monocytogenes in immunocompromised patients. Hence, the combination of ampicillin, vancomycin and third-generation cephalosporin is used for empirical therapy of bacterial meningitis.

  • 4.

    Bacillary dysentery: FQs are the drugs of choice. Some cases may respond to ampicillin, but many strains have developed resistance to it.

  • 5.

    Typhoid fever: A FQ or ceftriaxone is the drug of choice for typhoid. Ampicillin, cotrimoxazole or ciprofloxacin is useful for eradicating carrier state.

  • 6.

    Syphilis: Penicillin G is the drug of choice for syphilis. T. pallidum is very sensitive to penicillin and is killed at very low concentration of the drug. Procaine penicillin G/benzathine penicillin G is used for the treatment of early syphilis. For late syphilis, benzathine penicillin G is used. The alternative drugs are ceftriaxone, azithromycin and doxycycline. Penicillin is the drug of choice for treatment of syphilis in pregnancy.

  • 7.

    Diphtheria: It is an acute infection of upper respiratory tract caused by C. diphtheriae . It is treated mainly with the specific antitoxin. Penicillin G helps to eliminate carrier state. Patients allergic to penicillin are treated with erythromycin.

  • 8.

    Clostridial infections (tetanus and gas gangrene): The main treatment is neutralization of the toxin by using human tetanus immunoglobulin. For gas gangrene, penicillin G is used as an adjunct to antitoxin.

  • 9.

    Gonococcal infections: Penicillin was the drug of choice for gonococcal infections. Ampicillin with probenecid is effective against non-penicillinase-producing gonococcus. Because of the emergence of resistant organisms, penicillins are not preferred at present. Third-generation cephalosporins, ceftriaxone or cefixime are the drugs of choice for uncomplicated gonococcal infections.

  • 10.

    Other infections: Leptospirosis, anthrax, Lyme disease, actinomycosis, rat-bite fever, etc., are effectively treated with penicillin G.

  • 11.

    Anaerobic infections: Amoxicillin/ampicillin/penicillin V is used in combination with metronidazole for treatment of acute necrotizing gingivitis (trench mouth).

  • 12.

    H. pylori infection: Amoxicillin is used in combination with other drugs.

  • 13.

    Serious infections : Bacteraemias, pneumonias, UTI, burns, etc., by P. aeruginosa and Proteus are more effectively treated with piperacillin/ticarcillin than by carbenicillin. Carbenicillin indanyl is used orally for the treatment of UTI caused by P. aeruginosa and Proteus spp. Ticarcillin is used in combination with β-lactamase inhibitor and an aminoglycoside for the treatment of mixed nosocomial infection.

Drug interactions of penicillins : Probenecid competes with β-lactams (penicillins and cephalosporins) for active tubular secretion and retards their excretion, thereby increasing the plasma concentration as well as the duration of action of β-lactams. Hence, simultaneous administration of probenecid and penicillin is useful in the treatment of bacterial endocarditis and gonococcal infections to enhance the therapeutic efficacy of β-lactams.

β-Lactamase inhibitors ( table 11.8 ).

They are clavulanic acid, sulbactam and tazobactam. They structurally resemble β-lactam molecules. β-Lactamase inhibitors bind to β-lactamases and inactivate them. Coadministration of these drugs with β-lactams increases the activity of β-lactams by preventing them from enzymatic destruction.

Table 11.8 ■
β-Lactamase inhibitors and their uses
Preparation (brand name) Route(s) of administration Uses
  • 1.

    Clavulanic acid + amoxicillin

  • Oral, i.m., i.v.

  • Skin, soft-tissue, otitis media, respiratory and urinary tract infections caused by β-lactamase-producing strains of S. aureus , E. coli , H. influenzae and gonococci

  • 2.

    Clavulanic acid + ticarcillin

  • i.m., i.v.

  • Mixed nosocomial infections due to aerobic gram-negative bacilli, S. aureus and Bacteroides spp.

  • 3.

    Sulbactam + ampicillin

  • Oral, i.m., i.v.

  • Intra-abdominal and pelvic infections (mixed aerobic and anaerobic infections) due to β-lactamase-producing strains of S. aureus , gram-negative aerobes and anaerobes

  • 4.

    Tazobactam + piperacillin

  • i.v.

  • Severe infections caused by β-lactamase-producing strains of gram-negative bacilli

Clavulanic acid.

It is isolated from Streptomyces clavuligerus . It competitively and irreversibly inhibits β-lactamases produced by a wide range of gram-positive and gram-negative bacteria. After binding to the enzyme, clavulanic acid itself gets inactivated, hence called a ‘suicide’ inhibitor.

Cephalosporins

The first cephalosporins were obtained from a fungus, Cephalosporium acremonium . Later, semisynthetic cephalosporins were developed. Cephalosporins are β-lactam antibiotics with 7-aminocephalosporanic acid nucleus. The mechanism of action and development of resistance are similar to those of penicillins. Like penicillins, cephalosporins also inhibit synthesis of bacterial cell wall and produce bactericidal effect. Cephalosporins have been divided into five generations.

Important features of first, second, third and fourth generation cephalosporins have been described in Table 11.9 .

Fifth-generation cephalosporins: They are ceftaroline fosamil (i.v.) and ceftobiprole medocaril (i.v.). Both are prodrugs. They are active against gram-positive and gram-negative bacteria including MRSA, penicillin-resistant S. pneumoniae , Enterococcus fecalis , etc. They are indicated for treatment of complicated skin and soft-tissue infections and community-acquired pneumonia caused by resistant organisms.

Pharmacokinetics.

Cephalosporins are administered either orally or parenterally ( Table 11.9 ). These drugs are excreted mainly unchanged through kidney by either glomerular filtration or tubular secretion. Some cephalosporins are metabolized in the body before their excretion. Cefotaxime is deacetylated in the body before its excretion. Cefoperazone is mainly excreted through bile. Like penicillins, the active tubular secretion of cephalosporins is blocked by probenecid, resulting in higher blood levels and longer duration of action.

Table 11.9 ■
Antibacterial spectrum, pharmacokinetics and uses of cephalosporins
Cephalosporins First generation Second generation Third generation Fourth generation
  • 1.

    Drugs

  • Cephalexin (O)

  • Cefadroxil (O)

  • Cefazolin (i.m., i.v.)

  • Cephradine (O, i.m., i.v.)

  • Cephalothin (i.m.)

  • Cefaclor (O)

  • Cefuroxime axetil (O)

  • Cefuroxime (i.m., i.v.)

  • Cefoxitin (i.m., i.v.)

  • Cefotetan (i.m.)

  • Cefprozil (O)

  • Cefixime (O)

  • Cefpodoxime proxetil (O)

  • Ceftriaxone (i.m., i.v.)

  • Cefotaxime (i.m., i.v.)

  • Cefoperazone (i.m., i.v.)

  • Ceftazidime (i.m., i.v.)

  • Ceftizoxime (i.m., i.v.)

  • Cefdinir (O)

  • Ceftibuten (O)

  • Cefepime (i.v.)

  • Cefpirome (i.m., i.v.)

  • 2.

    Antibacterial spectrum

    • Against gram-positive organisms (except enterococci and MRSA)

    • Against gram-negative organisms

    • Anaerobes

    • Against Pseudomonas

    • Against Salmonella

  • +++

  • + ( E. coli , K. pneumoniae )

  • Effective against oral cavity anaerobes except Bacteroides fragilis

  • Not effective

  • Not effective

  • ++

  • ++ ( E. coli , K. pneumoniae , Proteus , H. influenzae )

  • Effective against anaerobes including B. fragilis (cefotetan, cefoxitin)

  • Not effective

  • Not effective

  • +

  • +++

  • Effective against anaerobes including B. fragilis (cefoperazone, ceftizoxime)

  • Effective (cefoperazone, ceftazidime)

  • Effective (ceftriaxone, cefoperazone)

  • +

  • +++

  • Not effective against B. fragilis

  • Effective (cefepime)

  • 3.

    β-Lactamase enzyme

  • Among the first-generation agents, cefazolin is highly susceptible to staphylococcal β-lactamases

  • Cefoxitin and cefuroxime are resistant to β-lactamases produced by gram-negative organisms

  • Most of them are resistant to most of the β-lactamases (except cefoperazone) produced by gram-negative organisms

  • Same as third generation

  • 4.

    Blood–brain barrier (BBB)

  • Some of the second-generation drugs (cefuroxime) cross BBB

  • Cefotaxime, ceftriaxone cross BBB and reach high concentration in CSF

  • Cross BBB

  • 5.

    Uses

  • 1.

    Skin and soft-tissue infections due to streptococci and Staphylococcus aureus

  • 2.

    Surgical prophylaxis: Cefazolin is preferred because of its longer duration of action

  • 1.

    Respiratory tract infections: Otitis media and sinusitis – oral cefuroxime axetil can be used

  • 2.

    Cefoxitin and cefotetan are preferred for mixed (gram-negative bacteria and anaerobes) intra-abdominal and pelvic infections

Third-generation cephalosporins alone or with aminoglycosides are used in severe gram-negative infections
  • 1.

    Pyelonephritis caused by gram-negative organisms: Ceftriaxone

  • 2.

    Community-acquired pneumonia: Ceftriaxone, cefotaxime

  • 3.

    Gonorrhoea: Ceftriaxone is the drug of choice, 250 mg i.m. as a single dose

  • 4.

    Typhoid fever: Ceftriaxone and cefoperazone are very effective for the treatment of multidrug-resistant Salmonella infections

  • 5.

    Meningitis caused by meningococci and Haemophilus influenzae: Inj. cefotaxime and ceftriaxone are the preferred drugs

  • 6.

    Mixed aerobic and anaerobic infections seen in patients with malignancy

  • 7.

    Septicaemia caused by gram-negative infections

  • 8.

    Nosocomial infection: Third-generation drugs are useful

  • 9.

    Syphilis: Ceftriaxone is an alternative drug

  • Same as third generation . They are reserve drugs for hospital-acquired resistant infections

+, less active; ++, moderately active; +++, highly active; CSF, cerebrospinal fluid; MRSA, methicillin-resistant S. aureus .

Adverse effects

  • 1.

    Hypersensitivity: The most common adverse effects are allergic reactions. They are skin rashes, urticaria and rarely anaphylaxis. Cross-reactivity to penicillin is seen in few patients.

  • 2.

    GI disturbances mainly diarrhoea, vomiting and anorexia can also occur.

  • 3.

    Pain at the site of i.m. injection mainly with cephalothin. Intravenous cephalosporins can cause thrombophlebitis.

  • 4.

    Nephrotoxicity is also seen, particularly with cephaloridine, because of which it has been withdrawn. Coadministration of cephalothin and gentamicin increases the risk of nephrotoxicity.

  • 5.

    Intolerance to alcohol (a disulfiram-like reaction) has been reported with cefotetan and cefoperazone.

  • 6.

    Severe bleeding can occur due to either hypoprothrombinaemia (which responds to vitamin K therapy) or thrombocytopenia and/or platelet dysfunction, especially in patients with renal failure.

Carbapenems

Examples are imipenem, meropenem, doripenem, ertapenem and faropenem.

Imipenem

Imipenem is a semisynthetic β-lactam antibiotic. Imipenem, like other β-lactam antibiotics, acts by inhibiting bacterial cell wall synthesis and produces bactericidal activity. It has a wide spectrum of antibacterial activity – gram-positive organisms like streptococci, staphylococci, enterococci, Listeria and C. difficile (anaerobe); and gram-negative organisms like P. aeruginosa , Enterobacteriaceae and B. fragilis (anaerobes). It is resistant to most β-lactamases.

Cilastatin, a dehydropeptidase inhibitor, increases the concentration of imipenem in urine. Hence, it is combined with imipenem. Imipenem–cilastatin combination increases the antibacterial efficacy.

Imipenem may exhibit cross-reactivity with penicillins and cephalosporins. Nausea, vomiting and skin rashes are the common side effects and, rarely, seizures have also been reported.

Other carbapenems

Meropenem and doripenem

  • Injected intravenously

  • Not destroyed by dehydropeptidase – does not require cilastatin coadministration

  • Seizures less likely

  • Also effective against imipenem-resistant P. aeruginosa

Ertapenem

  • Is administered parenterally (i.v. and i.m.)

  • Has longer half-life than those of imipenem and meropenem – once-daily dose is used

  • Less effective against P. aeruginosa

Faropenem

  • Orally effective

Uses of carbapenems

They are used for treatment of hospital-acquired infections – skin and soft-tissue, genitourinary, respiratory, abdominal infections, etc. Dose of carbapenems should be reduced in patients with renal failure.

Monobactams

Aztreonam is a β-lactam antibiotic with only one ring in its structure, hence the name monobactam. It also acts by inhibiting the bacterial cell wall synthesis. It is effective only against gram-negative bacteria, such as Enterobacteriaceae, P. aeruginosa , gonococci and H. influenzae , but has no activity against gram-positive bacteria and anaerobes. It is resistant to most β-lactamases. It is administered only parenterally (i.m., i.v.). The main advantage with aztreonam is lack of cross-reactivity with other β-lactam antibiotics (except with ceftazidime). It is useful for treatment of hospital-acquired gram-negative infections (genitourinary, intra-abdominal, etc.).

Aminoglycosides

They include streptomycin, gentamicin, tobramycin, amikacin, kanamycin, sisomicin, neomycin, framycetin, netilmicin and paromomycin.

Common properties of aminoglycosides

  • 1.

    They contain two or more amino sugars attached by glycosidic linkage to hexose ring.

  • 2.

    They are highly polar compounds, hence poorly absorbed from the GI tract. They are administered by parenteral route (i.m./i.v.) for systemic effect.

  • 3.

    They are mainly distributed into extracellular fluid and poorly penetrate into the CSF.

  • 4.

    They are not metabolized in the body.

  • 5.

    They are excreted unchanged in urine.

  • 6.

    They have bactericidal action against gram-negative aerobes and are more active at alkaline pH.

  • 7.

    They cause ototoxicity and nephrotoxicity .

  • 8.

    They exhibit partial cross-resistance among them.

  • 9.

    Transport of aminoglycosides into the bacterial cell requires oxygen; hence, anaerobes are resistant to aminoglycosides.

Mechanism of action.

Aminoglycosides are bactericidal agents – inhibit protein synthesis.

Mechanisms of bacterial resistance.

Bacterial resistance to aminoglycosides is due to (i) inactivation of the drug by bacterial enzymes, (ii) decreased entry of drug into bacterial cell and (iii) decreased affinity of the drug for the ribosomes.

Aminoglycosides exhibit

  • 1.

    A concentration-dependent killing effect – higher the plasma concentration, more of the bacteria killed rapidly.

  • 2.

    A postantibiotic effect – bactericidal effect is present even when serum concentration falls below MIC. Therefore, once-daily dosing regimen is effective.

Dosing

  • 1.

    Once-daily dosing regimen – total daily dose is given as a single injection. It is preferred because it:

    • Is as effective as multiple-dose regimen. Higher peak plasma concentration is achieved following single dose.

    • Is safer than multiple-dose regimen. The plasma trough concentration of aminoglycosides remains below threshold levels for toxicity for a long period of time.

    • Is convenient.

  • 2.

    Multiple-daily dosing regimen – the total daily dose is administered in two or three equally divided doses.

Once-daily dosing regimen is not preferred in bacterial endocarditis, children and patients with renal impairment. Dose adjustment of aminoglycosides is done according to body weight and creatinine clearance.

Adverse effects

  • 1.

    Ototoxicity: Vestibular and cochlear dysfunctions can occur due to VIII cranial nerve damage. Aminoglycosides get concentrated in the perilymph and endolymph of the inner ear which can lead to progressive damage to vestibular and cochlear hair cells. Streptomycin and gentamicin mainly affect vestibular function. Vestibular dysfunction causes intense headache (earliest symptom), dizziness, nausea, vomiting, vertigo, nystagmus and ataxia. Amikacin and kanamycin affect auditory function, causing more cochlear damage. The manifestations of cochlear damage are tinnitus (reversible on discontinuation of the drug) and deafness (permanent).

    • The important risk factors for ototoxicity are the following:

      • (a)

        Elderly patients

      • (b)

        Repeated courses of aminoglycosides

      • (c)

        Persistently increased concentration of the drug in plasma

      • (d)

        Patients with preexisting auditory impairment

      • (e)

        Concurrent use of other ototoxic drugs, such as vancomycin, minocycline and loop diuretics

  • 2.

    Nephrotoxicity: Aminoglycosides get concentrated in renal cortex and produce nephrotoxicity, which is usually reversible on discontinuation of the drug. The incidence of nephrotoxicity is highest with neomycin and least with streptomycin. There is a decrease in urinary concentrating capacity, albuminuria, etc. The risk factors for nephrotoxicity are elderly patients, preexisting renal disease and concurrent use of other nephrotoxic drugs, such as AMB, vancomycin, cisplatin and cyclosporine.

  • 3.

    Neuromuscular blocking effect: Apnoea and muscular paralysis have been reported. It may be reversed by administration of calcium salt. Aminoglycosides inhibit release of acetylcholine from motor nerve. Myasthenic patients are more susceptible to neuromuscular blocking effect of these drugs; hence, they should be avoided.

  • 4.

    Hypersensitivity reactions are rare; occasionally skin rashes, drug fever and eosinophilia can occur. Cross-sensitivity between aminoglycosides may occur.

  • 5.

    Use of aminoglycosides during pregnancy may cause ototoxicity in fetus.

Streptomycin

Streptomycin was the first aminoglycoside discovered in 1944. The common properties, mechanism of action and adverse effects are explained above.

Uses.

Streptomycin is one of the first-line drugs for TB and is used in combination with other antitubercular drugs. The other uses include tularaemia, plague and brucellosis.

Gentamicin

It is the most commonly used aminoglycoside antibiotic for aerobic gram-negative bacillary infections due to E. coli , Klebsiella , Proteus , Enterobacter and P. aeruginosa . It is also effective against gram-positive infections – enterococci, S. viridans and staphylococci but not M. tuberculosis . It is available for parenteral and topical administration. Common properties, mechanism of action and adverse effects are discussed above.

Neomycin

It is highly nephrotoxic, hence never used for systemic effect. It is used only for local effect. The common properties, mechanism of action and adverse effects are as for other aminoglycosides.

Uses of neomycin

  • Topically

    • (a)

      Infections of the skin and mucous membranes: Ulcers, wounds and burns.

    • (b)

      Infections of the eye and external ear: Neomycin is often used in combination with bacitracin or polymyxin B.

  • Orally (for local action)

    • (a)

      Neomycin sulphate is useful in combination with erythromycin base for preparation of bowel before abdominal surgery.

    • (b)

      Hepatic encephalopathy: Neomycin, on oral administration, reduces blood ammonia level by destroying the colonic bacteria. Neomycin is highly toxic; hence, it has been replaced by oral lactulose, which is preferred for hepatic encephalopathy.

Framycetin (soframycin)

Like neomycin, framycetin is also highly nephrotoxic, hence not used for systemic administration. The common properties, mechanism of action and adverse effects are similar to those of other aminoglycosides. Framycetin is widely used topically for skin, eye and ear infections.

Amikacin

Among the aminoglycosides, it has the broadest spectrum of activity. It is resistant to aminoglycoside-inactivating enzymes. It is useful for the treatment of nosocomial gram-negative infections and tuberculosis.

Tobramycin

All features are similar to those of gentamicin. It is superior to gentamicin against P. aeruginosa – useful in the treatment of serious infection by this organism.

Paromomycin

It is an aminoglycoside with activity against protozoans. It can be used in intestinal amoebiasis, giardiasis, vaginal trichomoniasis, visceral leishmaniasis and hepatic encephalopathy.

Netilmicin

It is resistant to aminoglycoside-inactivating enzymes, hence effective against most of the gentamicin-resistant bacteria.

Therapeutic uses of gentamicin and other aminoglycosides

Among aminoglycosides, gentamicin is the most commonly used because it is cheap and effective against most of the aerobic gram-negative bacilli.

  • 1.

    Severe aerobic gram-negative bacillary infections

    • Gentamicin, tobramycin, amikacin and netilmicin are effective against P. aeruginosa .

    • Amikacin and netilmicin are used for treatment of serious nosocomial infections due to gram-negative bacilli.

    • Aminoglycosides are often used in combination with penicillins/third-generation cephalosporins in these conditions.

  • 2.

    Bacterial endocarditis due to S. viridans and Enterococcus : Gentamicin is used in combination with a penicillin or vancomycin. Combination broadens the spectrum of activity, produces synergistic effect and decreases emergence of resistance.

    • Penicillin G + gentamicin for S. viridans .

    • Ampicillin + gentamicin for Enterococcus .

    • Vancomycin + gentamicin for Enterococcus (patients allergic to β-lactam antibiotics).

    • Gentamicin and ampicillin combination is also used for the prophylaxis of endocarditis in high-risk patients before surgical procedures.

  • 3.

    TB: Streptomycin, kanamycin and amikacin are used in the treatment of TB.

  • 4.

    Other gram-negative infections

    • Plague: Streptomycin/gentamicin is used intramuscularly.

    • Brucellosis: Streptomycin/gentamicin is used in combination with doxycycline.

    • Tularaemia: Streptomycin or gentamicin is the drug of choice. FQs and tetracyclines are also effective.

  • 5.

    Gentamicin, tobramycin, neomycin, sisomicin, framycetin, etc., are used topically for gram-negative skin, eye and ear infections.

Broad-spectrum antibiotics

Tetracyclines and chloramphenicol are broad-spectrum antibiotics. They are so called because of their effectiveness against a wide range of microorganisms, such as:

  • Gram-positive and gram-negative cocci – S. aureus , S. pneumoniae , N. gonorrhoeae

  • Gram-negative bacilli – V. cholerae , H. ducreyi , H. influenzae , H. pylori , Campylobacter , Yersinia pestis

  • Gram-positive bacilli – B. anthracis , Listeria , Clostridia , Propionibacterium acnes

  • Others – Rickettsiae , Mycoplasma , Chlamydia , Spirochetes , Actinomyces , Plasmodia , Entamoeba histolytica

Tetracyclines

Tetracyclines have four cyclic rings in their structure ( Fig. 11.8 ).

Fig. 11.8
Basic structure of tetracycline.

Mechanism of action

Resistance.

Bacterial resistance to tetracyclines is due to: (i) decreased influx or increased efflux of tetracyclines and (ii) inactivation of the drug by enzymes.

Pharmacokinetics.

The older tetracyclines are incompletely absorbed after oral administration ( Table 11.10 ), but that is adequate to produce antibacterial activity. Food interferes with the absorption of all tetracyclines; doxycycline and minocycline are less affected. Tetracyclines have chelating property, hence form stable insoluble and unabsorbable complexes with calcium, magnesium, iron and other metal ions. Therefore, the absorption of tetracyclines is reduced by simultaneous administration with dairy products, antacids, iron, sucralfate and zinc salts. Tetracyclines are widely distributed throughout the body, and get concentrated in liver, spleen, bone, dentine, enamel of unerupted teeth but concentration in CSF is relatively low. They cross placental barrier, and are metabolized in liver and excreted in urine. Doxycycline is excreted mainly in the faeces via bile. Therefore, doxycycline is safe for use in patients with renal insufficiency. Doxycycline undergoes enterohepatic cycling.

Table 11.10 ■
Important features of tetracyclines
Drugs Route of administration Absorption from the gut Half-life, t ½ (hours) Dosage
Oxytetracycline Tetracycline Oral, i.v., topical
Oral, topical
Incomplete 6–12 250–500 mg q.i.d.
Demeclocycline Oral Incomplete 16–18 300–600 mg b.d.
Doxycycline
Minocycline
Oral, i.v.Oral High 18–24 100 mg b.d. or o.d.

Adverse effects

  • 1.

    GI: On oral administration, they can cause GI irritation manifested as nausea, vomiting, epigastric distress, abdominal discomfort and diarrhoea. Diarrhoea is more common with tetracycline and oxytetracycline as they are incompletely absorbed → cause alteration of normal flora. Risk of diarrhoea is low with doxycycline.

  • 2.

    Phototoxicity: It is particularly seen with demeclocycline and doxycycline. They may also produce sunburn-like reaction in the skin on exposure to sunlight. They may also produce pigmentation of nails.

  • 3.

    Hepatotoxicity: Acute hepatic necrosis with fatty changes is common in patients receiving high doses (>2 g/day) intravenously. It is more likely to occur in pregnant women.

  • 4.

    Renal toxicity: Demeclocycline may produce nephrogenic diabetes insipidus by blocking the action of antidiuretic hormone (ADH) on collecting duct. This effect of demeclocycline has been used therapeutically in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

    • Fanconi syndrome: Use of outdated tetracyclines may damage proximal renal tubules – the patient may present with nausea, vomiting, polyuria, proteinuria, acidosis, etc.

  • 5.

    Superinfection: It is common with older tetracyclines because of their incomplete absorption in the gut; they cause alteration of the gut flora. Superinfection occurs with organisms like Candida , Proteus , Pseudomonas and C. difficile . Pseudomembranous colitis caused by C. difficile is a serious complication. It is characterized by severe diarrhoea, fever, abdominal pain and stool mixed with blood and mucus, which is treated with oral metronidazole.

  • 6.

    Effects on bones and teeth: Tetracyclines have calcium chelating property and form tetracycline–calcium orthophosphate complex which is deposited in growing bone and teeth. Use of tetracyclines in children and during pregnancy can cause permanent brownish discolouration of deciduous teeth due to deposition of chelate in the teeth. There is increased incidence of caries in such teeth. Tetracyclines also affect the linear growth of bones. The incidence of hepatotoxicity is more in pregnant women. Therefore, tetracyclines are contraindicated during pregnancy in the interest of both fetus and mother. It is also contraindicated in children up to the age of 8 years.

  • 7.

    They may cause increased intracranial pressure (pseudotumour cerebri) in infants.

  • 8.

    Hypersensitivity reactions: Skin rashes, fever, urticaria, exfoliative dermatitis, etc., may occur rarely. Cross-sensitivity among tetracyclines is common.

Therapeutic uses

  • 1.

    Rickettsial infections: Tetracyclines are the first-choice drugs for the treatment of rickettsial infections – epidemic typhus, Rocky Mountain spotted fever, scrub typhus, rickettsial pox and Q fever. Doxycycline 100 mg b.d. is given orally or intravenously for 5–7 days.

  • 2.

    Mycoplasma pneumoniae infections : Doxycycline has good activity against Mycoplasma – used to shorten the duration of illness. It is a first choice drug in atypical pneumonia due to M. pneumoniae .

  • 3.

    Chlamydial infections

    • Lymphogranuloma venereum: It is a sexually transmitted infection caused by C. trachomatis . Doxycycline is the drug of choice. In complicated cases (i.e. pelvic inflammatory disease), doxycycline 100 mg b.d. should be continued for 21 days. Macrolides are also effective.

    • Chlamydial urethritis and granuloma inguinale: Doxycycline is highly effective and is the drug of choice.

    • Psittacosis: Doxycycline is the preferred agent; treatment should be continued for 2 weeks to prevent relapse.

  • 4.

    Cholera: Fluid and electrolyte replacement is the mainstay of therapy. Single dose of tetracycline 2 g or doxycycline 300 mg is effective in adults. It reduces the stool volume.

  • 5.

    Brucellosis: Treatment of choice is a combination of doxycycline with rifampin/gentamicin/streptomycin.

  • 6.

    Plague: Doxycycline is highly effective for treatment of plague.

  • 7.

    As an alternative drug: For treatment of leptospirosis (doxycycline is an alternative to penicillins), pneumonia due to Chlamydia pneumoniae (doxycycline alternative to azithromycin), tularaemia (alternative to streptomycin, gentamicin), etc.

  • 8.

    Acne: Low doses of tetracyclines are used.

    • Tetracyclines act by inhibiting propionibacteria, thereby prevent the formation of free fatty acids.

  • 9.

    Malaria: Doxycycline is used in combination with other antimalarial agents for treatment of chloroquine-resistant P. falciparum malaria. It is used alone for malarial chemoprophylaxis.

  • 10.

    Amoebiasis: See p. 452.

  • 11.

    SIADH: Demeclocycline has anti-ADH action; hence, it is used in SIADH to promote diuresis.

  • 12.

    Leprosy: It is one of the components in ROM (rifampin, ofloxacin and minocycline) regimen for single-lesion paucibacillary leprosy (PBL).

  • 13.

    Filariasis : Doxycycline is given orally in filarial infection.

Advantages of doxycycline over tetracycline

  • 1.

    It can be administered orally as well as intravenously.

  • 2.

    It is highly potent.

  • 3.

    It is completely absorbed after oral administration.

  • 4.

    Food does not interfere with its absorption.

  • 5.

    It has a longer duration of action ( t ½ – 24 hours); requires less frequent dosing subscript

  • 6.

    Incidence of diarrhoea is rare as it does not affect the intestinal flora.

  • 7.

    It can be safely given to patients with renal failure, as it is excreted primarily in bile.

Tigecycline

The spectrum of activity of tigecycline is similar to that of tetracyclines. It is also effective against organisms resistant to tetracyclines. Mycobacteria are also susceptible. Tigecycline has a long half-life. It is administered intravenously. Adverse effects include nausea and vomiting. It can cause brown discolouration of the teeth in children. It is useful in serious skin, soft-tissue and intra-abdominal infections.

Chloramphenicol

Chloramphenicol, a broad-spectrum antibiotic; was isolated from Streptomyces venezuelae . Even though chloramphenicol has a broad spectrum of antibacterial activity, its use is limited to only a few conditions because of its dangerous side effect – bone marrow suppression.

Mechanism of action

Chloramphenicol is a bacteriostatic agent, but in high concentration, it can be bactericidal against H. influenzae , N. meningitidis and S. pneumoniae . It can also inhibit mitochondrial protein synthesis in mammalian cells by acting on 70S ribosomes.

Resistance to chloramphenicol is caused by:

  • 1.

    Production of inactivating enzyme – acetyltransferase, e.g. H. influenzae , S. typhi , S. aureus

  • 2.

    Decreased permeability of the microbial cell wall

  • 3.

    Ribosomal mutation

Pharmacokinetics.

Chloramphenicol is commonly given by oral route and is rapidly absorbed from the gut. It is also available for parenteral and topical administration. It has a bitter taste; to improve the taste, chloramphenicol palmitate suspension has been developed for paediatric use. It gets activated in the intestine by pancreatic lipase. Chloramphenicol is widely distributed to all tissues including CSF and brain. It also crosses placental barrier and is secreted in milk. It gets metabolized in liver by glucuronide conjugation and the metabolite is excreted mainly in urine.

Adverse effects.

Most of the adverse effects of chloramphenicol are due to inhibition of mammalian mitochondrial protein synthesis.

  • 1.

    Hypersensitivity reactions: Skin rashes, drug fever and angioedema may occur rarely.

  • 2.

    Bone marrow suppression: The most serious adverse effect of chloramphenicol is on bone marrow. It can occur in two ways:

    • (a)

      Dose-dependent reversible suppression of bone marrow, which manifests as anaemia, leucopenia and thrombocytopenia

    • (b)

      Idiosyncratic non-dose-related irreversible aplastic anaemia, which is often fatal

  • 3.

    GI effects: These include nausea, vomiting and diarrhoea. Prolonged use may cause superinfection due to suppression of gut flora.

  • 4.

    Gray baby syndrome: In neonates, especially in premature babies, chloramphenicol can cause a dose-related gray baby syndrome due to reduced degradation and detoxification of the drug in liver because of the deficiency of glucuronyl transferase enzyme. The manifestations are nausea, vomiting, abdominal distension, diarrhoea, refusal to suck, cyanosis, irritability and circulatory collapse. The skin appears ashen gray colour, hence the name ‘gray baby’ syndrome. Mortality is high. Therefore, chloramphenicol should be avoided in neonates.

Drug interactions : Like erythromycin, chloramphenicol increases plasma concentration of certain drugs, such as warfarin, phenytoin, rifabutin and antiretroviral protease inhibitors (PIs), by inhibiting hepatic cytochrome P450 isoenzymes.

Therapeutic uses

  • 1.

    Typhoid fever: Chloramphenicol was the first-choice drug for typhoid. Antibiotics useful in typhoid are third-generation cephalosporins, FQs, azithromycin, ampicillin, cotrimoxazole, etc. Now, FQs (ciprofloxacin, ofloxacin, levofloxacin, etc.) or third-generation cephalosporins (ceftriaxone, cefoperazone) are the drugs of choice for typhoid fever. The dose of ciprofloxacin is 750 mg 12 hourly for 10 days. It also eliminates carrier state. MDR cases are treated with ceftriaxone (2–4 g i.v. daily for 10 days) or azithromycin.

  • 2.

    Bacterial meningitis: Third-generation cephalosporins are the preferred drugs for the treatment of bacterial meningitis caused by H. influenzae , N. meningitidis and S. pneumoniae . However, chloramphenicol can be used alone or in combination with ampicillin.

  • 3.

    Anaerobic infections: Chloramphenicol is effective against most anaerobic bacteria including B. fragilis . It is often used in combination with metronidazole for the treatment of brain, lung, intra-abdominal or pelvic abscesses.

  • 4.

    Rickettsial infections: Tetracyclines are the drugs of choice for the treatment of rickettsial diseases. Chloramphenicol can be used to treat rickettsial infections in children and pregnant women.

  • 5.

    Eye and ear infections: Chloramphenicol is used topically for eye and ear infections due to susceptible organisms.

  • 6.

    Brucellosis : Chloramphenicol can be used when tetracyclines are contraindicated.

Macrolides

Erythromycin was obtained from Streptomyces erythreus . Roxithromycin, clarithromycin and azithromycin are semisynthetic macrolides. Erythromycin is active against S. pyogenes , S. pneumoniae , N. gonorrhoea , C. perfringens , C. diphtheriae , Listeria , Mycoplasma , Legionella , C. trachomatis , B. pertussis , etc. It is not effective against B. fragilis .

Mechanism of action.

E rythromycin and other macrolides bind to bacterial 50S ribosomal subunit and inhibit protein synthesis. They are bacteriostatic, but at high concentrations, they can act as bactericidal agents. They are more active at alkaline pH.

Pharmacokinetics.

Erythromycin is adequately absorbed from the upper GI tract. It is destroyed by gastric acid (acid labile), hence must be administered as E nteric-coated tablets to protect it from gastric acid. Food may delay the absorption of erythromycin. It is widely distributed in the body and reaches therapeutic concentration in prostatic secretions but does not cross BBB. It is partly metabolized in liver and excreted in bile.

Preparations of erythromycin.

They are erythromycin base, E rythromycin E stolate and erythromycin stearate.

Adverse effects

  • 1.

    The common side effects are related to the GI tract ( E nteral toxicity): Nausea, vomiting, epigastric pain and diarrhoea. Erythromycin increases GI motility by stimulating motilin receptors in the gut.

  • 2.

    Hypersensitivity reactions: Skin rashes, drug fever, eosinophilia and hepatitis with cholestatic jaundice, particularly with erythromycin estolate. Incidence of hepatotoxicity is more in pregnant women.

Drug interactions.

Erythromycin and clarithromycin are E nzyme inhibitors, hence increase the blood levels of a number of drugs, such as theophylline, carbamazepine, valproate, warfarin, digoxin and cyclosporine, and potentiate their effects. Erythromycin and clarithromycin can precipitate fatal ventricular arrhythmias when given with cisapride, astemizole, terfenadine, etc. – such interactions are not seen with azithromycin.

Drawbacks of erythromycin

  • 1.

    It has a narrow spectrum of antibacterial activity.

  • 2.

    Its oral bioavailability is low.

  • 3.

    It has a short duration of action.

  • 4.

    Poor patient compliance due to GI side effects.

To overcome the above drawbacks, semisynthetic macrolides – roxithromycin, clarithromycin and azithromycin – have been developed ( Table 11.11 ).

Table 11.11 ■
Comparative features of macrolides
Erythromycin Roxithromycin Clarithromycin Azithromycin
  • 1.

    Source

  • Natural

  • Semisynthetic

  • Semisynthetic

  • Semisynthetic

  • 2.

    Duration of action

  • Short-acting (6 hours)

  • Long-acting (12 hours)

  • Long-acting

  • Long-acting

  • 3.

    GI absorption

  • Incomplete

  • Good

  • Good, but undergoes first-pass metabolism

  • Good

  • 4.

    Acid labile/stable

  • Acid labile, hence administered as enteric-coated tablets

  • Acid stable

  • Acid stable

  • Acid stable

  • 5.

    Antibacterial spectrum and therapeutic uses

  • Narrow spectrum

  • Uses (see below)

  • Almost similar to erythromycin

  • Expanded antibacterial spectrum – effective against Mycobacterium avium complex (MAC), Mycobacterium leprae , Helicobacter pylori , T. gondii , etc., in addition to organisms sensitive to erythromycin

  • Expanded antibacterial spectrum – effective against MAC, H. influenzae , Salmonella , malaria, T. gondii , etc., in addition to organisms sensitive to erythromycin

  • 6.

    Dosage and duration of therapy

  • 250–500 mg oral q.i.d. for 7 days

  • 150 mg b.d. half an hour before food for 7 days

  • 250 mg b.d. for 1–2 weeks

  • 500 mg o.d. 1 hour before or 2 hours after food for 3–5 days

  • 7.

    Enzyme inhibitor

  • Causes various drug interactions

  • Drug interactions are rare

  • Yes; drug interactions are same as for erythromycin

  • Drug interactions are rare

GI, gastrointestinal.

Clarithromycin ( table 11.11 )

Mechanism of action and spectrum of activity is similar to that of erythromycin. It is administered orally. It achieves high concentration inside the cells. It is also used for the treatment of MAC, leprosy and H. pylori infection. The uses are mentioned on p. 404.

Azithromycin ( table 11.11 )

It can be administered orally and intravenously. Oral administration should be either 1 hour before or 2 hours after food. It does not cross BBB. Azithromycin is more active against H. influenzae than erythromycin and clarithromycin ( Table 11.11 ). It is well absorbed, has wide tissue distribution and achieves high intracellular concentration than erythromycin. It is better tolerated and longer acting (single daily dose) than erythromycin.

Antibacterial spectrum and therapeutic uses of macrolides

  • 1.

    As a drug of choice in the following conditions:

    • (a)

      M. pneumoniae infections: Azithromycin and clarithromycin are often used for the treatment of community-acquired pneumonia. Erythromycin can also be used.

    • (b)

      Legionnaires’ pneumonia: Macrolides, especially azithromycin, is the drug of choice because of high tissue concentration, excellent activity, better tolerability and single daily dosing.

    • (c)

      Chlamydial infections: Azithromycin is the first choice drug in urethritis, lymphogranuloma venereum and chlamydial pneumonia. Macrolides are preferred for chlamydial infections in children and pregnant women.

    • (d)

      Diphtheria: Erythromycin is very effective for eliminating the carrier state and for the treatment of acute infection.

    • (e)

      Pertussis (whooping cough): Erythromycin is most effective for the treatment as well as for prophylaxis of close contacts. Clarithromycin and azithromycin are also effective.

    • (f)

      Chancroid: Azithromycin is effective as single dose in chancroid.

  • 2.

    As an alternative drug in patients who are allergic to penicillins/cephalosporins

    • (a)

      Tetanus: Administration of human tetanus antitoxin, tetanus toxoid, anticonvulsant (e.g. diazepam) and debridement of wound are important therapeutic measures. A course of oral erythromycin for 10 days may be given to eradicate C. tetani .

    • (b)

      Streptococcal infections: Tonsillitis, pharyngitis, otitis media, cellulitis, pneumonia, etc., respond to azithromycin and erythromycin.

    • (c)

      MDR typhoid fever: It is an alternative to cephalosporins.

    • (d)

      Prophylactic uses

      • Before surgical procedures to prevent bacterial endocarditis in patients with valvular lesion – azithromycin or clarithromycin can be used.

      • For prophylaxis of recurrences of rheumatic fever.

  • 3.

    Other Uses. For treatment of MAC infections in AIDS patients, azithromycin/clarithromycin is used in combination with other drugs. Clarithromycin is also useful in the treatment of H. pylori infection and leprosy along with other drugs.

Ketolides

Ketolides (e.g. telithromycin) are semisynthetic derivatives of erythromycin.

  • Spectrum of activity and site of action is similar to that of azithromycin. Also effective against some macrolide-resistant organisms.

  • Used orally for community-acquired pneumonia.

  • Hepatotoxicity is a serious adverse effect.

Spiramycin

It is a macrolide. Spectrum of activity is similar to that of erythromycin. It is used mainly to prevent transmission of Toxoplasma gondii from mother to fetus.

Miscellaneous antibacterial agents (see table 11.12 )

Classification

  • 1.

    Lincosamides: Clindamycin

  • 2.

    Streptogramins: Quinupristin/dalfopristin

  • 3.

    Oxazolidinones: Linezolid

  • 4.

    Glycopeptides: Vancomycin, teicoplanin

  • 5.

    Aminocyclitols: Spectinomycin

  • 6.

    Lipopeptides: Daptomycin

  • 7.

    Others: Bacitracin, polymyxin B, colistin, mupirocin, fusidic acid

Table 11.12 ■
Miscellaneous antibacterial agents (see also Figs 11.9 and 11.10 )
Drug with mechanism of action Antibacterial spectrum Pharmacokinetics Uses Adverse effects
  • Clindamycin (lincosamide) inhibits protein synthesis by binding to 50S subunit of bacterial ribosomes ( bacteriostatic )

  • Gram-positive cocci, anaerobes (including Bacteroides fragilis ), P. jiroveci , T. gondii

  • Administered by oral, i.m., i.v. and topically; widely distributed in the body including bones, poorly crosses BBB

  • 1.

    Anaerobic infections due to B. fragilis (pelvic, abdominal and lung abscess)

  • 2.

    In AIDS patients

    • (a)

      For P. jiroveci pneumonia in combination with primaquine

    • (b)

      For toxoplasmosis in combination with pyrimethamine

  • 3.

    Acne vulgaris – topically or orally

  • Skin rashes

  • Pseudomembranous colitis (superinfection) – diarrhoea with blood and mucus in the stools due to Clostridium difficile

  • The drug should be stopped immediately. It is treated with metronidazole (drug of choice) or vancomycin

  • Quinupristin/dalfopristin (streptogramins): They inhibit protein synthesis by binding to 50S ribosomal subunit (synergistic combination)

  • bactericidal – streptococci and staphylococci

  • bacteriostatic – E. faecium

  • Gram-positive cocci including MRSA and some VRE

  • Administered only by i.v. infusion

  • 1.

    Vancomycin-resistant enterococcal ( E. faecium ) infections (VRE)

  • 2.

    Nosocomial pneumonia due to MRSA

  • Pain due to thrombophlebitis, arthralgias and myalgias. It is an enzyme inhibitor and may raise the plasma levels of coadministered drugs (macrolides, fosphenytoin, fluoxetine, haloperidol, etc.)

  • Linezolid: Inhibits protein synthesis by binding to 50S ribosomal subunit; bacteriostatic except against streptococci (bactericidal )

  • Gram-positive organisms – streptococci, staphylococci including MRSA, VRSA, VRE, Listeria

  • Administered by oral and i.v. infusion

  • Skin and soft-tissue infections, nosocomial (hospital-acquired) pneumonia, urinary tract infection, etc., caused by VRE, MRSA and VRSA

  • GI side effects – nausea, vomiting and diarrhoea, headache, bone marrow suppression with anaemia, leucopenia and pancytopaenia occasionally

  • Tedizolid : Mechanism of action is similar to that of linezolid

  • Gram-positive organisms – streptococci, staphylococci including MRSA, VRE

  • Oral, i.v.

  • Skin and soft-tissue infections, nosocomial (hospital-acquired) pneumonia

  • Haematological adverse effects and neuropathy are less than in linezolid

  • Vancomycin: Inhibits bacterial cell wall synthesis (bactericidal)

  • Gram-positive cocci: S. aureus including MRSA, S. epidermidis , S. pyogenes , S. pneumoniae , S. viridans and Enterococcus . Gram-positive bacilli: diphtheroids and Clostridium spp.

  • Poorly absorbed after oral administration, hence used intravenously for systemic infections. Orally for antibiotic associated colitis (for local action)

  • 1.

    MRSA infections: Pneumonia, endocarditis, osteomyelitis, etc.

  • 2.

    Endocarditis due to S. viridans or enterococci: Vancomycin is used in combination with aminoglycoside in patients allergic to penicillin

  • 3.

    It is used with ampicillin and third-generation cephalosporin for empirical treatment of bacterial meningitis

  • 4.

    Orally for pseudomembranous colitis caused by C. difficile or staphylococci

  • Highly toxic, causes ototoxicity, nephrotoxicity and hypersensitivity reactions (skin rashes and anaphylaxis). Rapid i.v. infusion may cause shock-like state with flushing, fever, chills, tachycardia and hypotension –’red man’ syndrome due to release of histamine

  • Teicoplanin: Inhibits bacterial cell wall synthesis ( bactericidal )

  • Similar to that of vancomycin

  • Administered by i.m. or i.v. route

  • MRSA and enterococcal infections; for severe infections, teicoplanin is used in combination with gentamicin

  • Skin rashes, drug fever and rarely hypersensitivity reactions may occur

  • Bacitracin : Inhibits bacterial cell wall synthesis ( bactericidal )

  • Mainly against gram-positive cocci and bacilli

  • Highly nephrotoxic on parenteral administration, hence used only topically

  • Used topically for eye and skin infections – usually in combination with neomycin and/or polymyxin B

  • Rarely may cause hypersensitivity reactions

  • Spectinomycin : Inhibits protein synthesis by binding to 30S ribosomal subunit ( bacteriostatic )

  • Gram-negative bacteria

  • Given intramuscularly 2 g as a single dose

  • 1.

    For gonococcal infections in patients who are allergic to β-lactam antibiotics

  • 2.

    Multidrug-resistant gonococcal infections

  • 3.

    Can be used in pregnancy to treat gonococcal infections if patient is allergic to β-lactams

  • Skin rashes, fever and pain at injection site

  • Polymyxin B and colistin : Bind to membrane phospholipids of gram-negative bacteria → form pseudopores → leakage of cell contents → death of the bacilli ( bactericidal )

  • Gram-negative bacteria

  • Administered topically

  • 1.

    Used topically for skin, eye and ear infections due to gram-negative organism, often in combination with other AMAs (polymyxin B, bacitracin and neomycin)

  • 2.

    Orally in diarrhoeas due to gram-negative organisms – Salmonella , Shigella , E. coli

  • GI symptoms on oral administration

Fusidic acid: Inhibits bacterial protein synthesis (bacteriostatic) Gram-positive bacteria including S. aureus Topically Used topically for staphylococcal infections – boils, folliculitis, angular cheilitis, etc. Skin rashes
Mupirocin: Inhibits bacterial protein synthesis (bacteriostatic) Gram-positive bacteria including MRSA, S. pyogenes Topically Used for impetigo, burns, open wounds and ulcers Irritation and burning
AMA, antimicrobial agent; BBB, blood–brain barrier; GI, gastrointestinal; MRSA, methicillin-resistant S. aureus ; VRE, vancomycin-resistant Enterococcus ; VRSA, vancomycin-resistant S. aureus .
Fig. 11.9
AMAs inhibit protein synthesis by binding to either 50S or 30S ribosomal subunit.
Fig. 11.10
AMAs that inhibit bacterial cell wall synthesis.

Urinary antiseptics PH1.48

Some AMAs on oral administration attain high concentration only in the urinary tract and exert antibacterial activity locally. They are used to treat infections of the urinary tract and are called urinary antiseptics. Common organisms involved in UTI are E. coli , Proteus , Klebsiella and Pseudomonas.

Methenamine

Methenamine is a prodrug. In acidic urine, it is hydrolyzed to ammonia and formaldehyde.

Formaldehyde inhibits both gram-positive and gram-negative organisms and produces bactericidal activity. It is ineffective against urea-splitting microorganisms (e.g. Proteus spp.) as it increases urinary pH. To prevent the release of formaldehyde in the stomach, methenamine is administered as enteric-coated tablets. It is useful mainly for chronic suppressive therapy in recurrent UTI particularly if the causative organism is E. coli . Methenamine is contraindicated in patients with hepatic insufficiency because of the release of ammonia. The adverse effects are nausea, vomiting, diarrhoea and even haematuria with high doses.

Nitrofurantoin

It is a bacteriostatic agent and is more active in acidic pH. It is effective for the prophylaxis of UTI due to E. coli . It stains the urine brown. The common adverse effects are nausea, vomiting and diarrhoea. The hypersensitivity reactions include fever, leucopenia, anaemia, cholestatic jaundice, acute pneumonitis and rarely polyneuropathy.

Phenazopyridine

It is not an AMA. It is a dye and has analgesic action in urinary tract. It relieves pain, burning, urgency and frequency of urination associated with cystitis. It makes the urine orange red, which is harmless. Occasionally, it may cause nausea and vomiting.

Treatment of urinary tract infection

Treatment schedules (empirical therapy)

Acute cystitis

  • Ciprofloxacin 250–500 mg b.d. oral for 3 days

  • Norfloxacin 400 mg b.d. oral for 3 days

  • Ofloxacin 200 mg b.d. oral for 3 days

  • Cefpodoxime proxetil 200 mg b.d. for 3–5 days

  • Cotrimoxazole DS b.d. oral for 3 days

  • Nitrofurantoin 100 mg b.d. for 5 days

Acute pyelonephritis

  • Ampicillin 1 g q6h i.v. and gentamicin 1 mg/kg q8h i.v. for 3 weeks

  • Ciprofloxacin 750 mg q12h oral for 3 weeks

  • Ofloxacin 200 mg q12h oral for 3 weeks

  • Cotrimoxazole DS q12h oral for 3 weeks

Chronic pyelonephritis.

Drug regimen is similar to that for acute pyelonephritis, but duration of treatment is 3–6 months.

Drugs useful in the treatment of sexually transmitted diseases PH1.48

The mechanism of action, pharmacokinetics and adverse effects of individual drugs are described in respective chapters. The important drug regimens are given in Table 11.13 .

Table 11.13 ■
Important treatment regimens for sexually transmitted diseases
Disease Treatment schedule
Gonorrhoea Ceftriaxone 125 mg i.m., single dose
Or
Cefixime 400 mg oral, single dose
Or
Azithromycin 1 g oral, single dose
Syphilis Benzathine penicillin G 2.4 MU, i.m., single dose
Or
Doxycycline 100 mg oral, b.d. for 2 weeks
Or
Inj. ceftriaxone 1 g i.m. daily for 1 week
Lymphogranuloma venereum Doxycycline 100 mg oral, b.d. for 3 weeks
Or
Azithromycin 1 g oral, once weekly for 3 weeks
Granuloma inguinale Doxycycline 100 mg oral, b.d. for 3 weeks
Or
Azithromycin 1 g oral, once weekly for 3 weeks
Or
Ciprofloxacin 750 mg oral, b.d. for 3 weeks
Chancroid Azithromycin 1 g oral, single dose
Or
Ceftriaxone 250 mg i.m., single dose
Or
Ciprofloxacin 500 mg oral, b.d. for 3 days

Antipseudomonal agents (drugs used in pseudomonal infections)

β -Lactam antibiotics

  • Antipseudomonal penicillins – carbenicillin, carbenicillin indanyl, ticarcillin, piperacillin, mezlocillin

  • Cephalosporins – cefoperazone, ceftazidime, cefepime

  • Carbapenems – imipenem, meropenem, doripenem

  • Monobactams – aztreonam

Aminoglycosides.

Gentamicin, amikacin, tobramycin, netilmicin, sisomicin.

Fluoroquinolones.

Ciprofloxacin, levofloxacin.

Sulphonamides.

Silver sulfadiazine, *

* Topical agents.

mafenide. *

Others.

Polymyxin B, * colistin. *

Drugs used in anaerobic infections

Nitroimidazoles.

Metronidazole, tinidazole.

β -Lactam antibiotics

  • Penicillins – piperacillin with tazobactam; ticarcillin with clavulanic acid

  • Cephalosporins – cefoxitin, cefotetan, ceftizoxime

  • Carbapenems – imipenem, ertapenem, meropenem, doripenem

Fluoroquinolones.

Moxifloxacin.

Broad-spectrum antibiotics.

Tigecycline, chloramphenicol.

Sulphonamides.

Mafenide. *

Others.

Vancomycin, clindamycin.

Drugs used in typhoid fever

  • Third-generation cephalosporins: Ceftriaxone and cefoperazone are very effective for the treatment of MDR Salmonella infections. Injection ceftriaxone is injected intravenously in a dose of 2–4 g daily for 7–10 days. It is also effective to eliminate carrier state.

  • Fluoroquinolones: Ciprofloxacin (750 mg orally twice daily for 10 days) is the preferred drug for the treatment of typhoid. It causes rapid resolution of symptoms. Levofloxacin and ofloxacin can also be used. These agents are also effective in eliminating chronic carrier state of S. typhi , when therapy is continued for 4 weeks, as they attain effective concentration in bile and intestinal mucosa. FQs are contraindicated in children and pregnant women.

  • Azithromycin: It is used in cases of MDR typhoid fever. It is administered orally 500 mg daily for 7 days.

  • Chloramphenicol: It was the first choice drug for typhoid. It is no longer used now.

  • Cotrimoxazole: It is rarely used now.

Agents used in staphylococcal infections

  • Penicillins: Penicillinase-resistant penicillins – methicillin, cloxacillin, dicloxacillin

  • Cephalosporins: Cefprozil, cefpodoxime proxetil, cefepime

  • Carbapenems: Imipenem, meropenem, faropenem, doripenem

  • Tigecycline

  • Aminoglycoside : Netilmicin

  • Rifampin

  • Miscellaneous antibiotics : Vancomycin, teicoplanin, clindamycin, streptogramins (quinupristin/dalfopristin), linezolid

Drugs for MRSA.

Clindamycin, doxycycline, minocycline, tigecycline, linezolid, vancomycin, streptogramins, daptomycin, ceftaroline, teicoplanin.

Antituberculosis drugs PH1.44, PH1.45

Tuberculosis (TB) is a chronic infectious disease caused by M. tuberculosis .

Mycobacterial infections require prolonged treatment. Since TB is a chronic infection, it consists of excessive fibrous tissue with central necrosis. So vascularity of the lesion is poor; hence, the penetration of the drug into the lesion is decreased.

Classification

  • 1.

    First-line antitubercular drugs (standard drugs) : Isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), streptomycin (S)

  • 2.

    Second-line antitubercular drugs (reserve drugs) : para -Aminosalicylic acid (PAS), thiacetazone, cycloserine, ethionamide, kanamycin, capreomycin, amikacin, levofloxacin, moxifloxacin, ofloxacin, clarithromycin, rifabutin, rifapentine

Another form of classification is shown in Table 11.14 .

Table 11.14 ■
Antituberculosis drugs
Groups Drugs
First-line drugs (oral) Isoniazid, rifampin, ethambutol, pyrazinamide
Parenterally (injections) administered drugs Streptomycin, kanamycin, amikacin, capreomycin, viomycin
Fluoroquinolones Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin (Mfx)
Second-line drugs (oral) Ethionamide, prothionamide, cycloserine, terizidone, para -aminosalicylic acid, rifabutin, rifapentine
Drugs with doubtful/unproven efficacy Clofazimine, linezolid, amoxicillin/clavulanate, thioacetazone, imipenem/cilastatin, high-dose isoniazid (high-dose H), clarithromycin, bedaquiline
Note : Treatment of tuberculosis is based on WHO guidelines, 2008 and 2010.

First-line antituberculosis drugs ( table 11.15 ) PH1.44

They are cheap, more effective, routinely used and less toxic.

Table 11.15 ■
First line antituberculosis drugs and their daily doses (WHO 2010 guidelines)
Drug Daily dose (mg/kg)
Isoniazid (H) 5 (4–6)
Rifampin (R) 10 (8–12)
Pyrazinamide (Z) 25 (20–30)
Ethambutol (E) 15 (15–20)
Streptomycin (S) 15 (12–18)

Isoniazid (isonicotinic acid hydrazide [INH]).

Isoniazid is a highly effective and the most widely used antitubercular agent. It is orally effective, cheapest and has tuberculocidal activity. It is active against both intracellular and extracellular bacilli. It is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of TB (see p. 419).

Mechanism of action.

Isoniazid inhibits biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall.

Pharmacokinetics.

INH is readily absorbed from the gut, distributed well all over the body, tubercular cavities and body fluids like CSF, and also crosses placental barrier. It is metabolized by acetylation and the metabolites are excreted in urine. The rate of acetylation of INH is under genetic control resulting in either rapid or slow acetylators.

Uses.

Isoniazid (INH) is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of tuberculosis.

Adverse effects and drug interactions

  • 1.

    Hepatotoxicity: The risk of hepatic damage is more in chronic alcoholics, elderly patients and rapid acetylators. It is reversible on discontinuation of the drug. Patients receiving INH should be monitored for symptoms like anorexia, nausea, vomiting and jaundice.

  • 2.

    Peripheral neuritis: It is a dose-related toxicity. Isoniazid is structurally similar to pyridoxine; hence, INH competitively interferes with utilization of pyridoxine. It also promotes the excretion of pyridoxine. Peripheral neuritis is more common in slow acetylators. Pyridoxine 10 mg/day is generally given along with INH to reduce the risk of peripheral neuritis in alcoholics, diabetic patients and HIV-positive patients receiving antitubercular therapy. It is also used for the treatment (100 mg/day) of INH-induced peripheral neuritis.

  • 3.

    Other side effects are fever, skin rashes, arthralgia, anaemia, GI disturbances, psychosis and rarely convulsions.

Isoniazid inhibits the metabolism of phenytoin, carbamazepine, warfarin, etc. → increases plasma levels of these drugs → may result in toxicity.

Rifampin (rifampicin).

Rifampin is a derivative of rifamycin and is a first-line antitubercular drug. It rapidly kills intracellular and extracellular bacilli including spurters (those residing in caseous lesion). It is the only agent that can act on all types of bacillary subpopulations; hence, it is called sterilizing agent.

Mechanism of action.

Rifampin binds to bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis. It has bactericidal effect against mycobacteria, N. meningitidis , H. influenzae , S. aureus , E. coli , Pseudomonas , etc.

Pharmacokinetics.

It is given orally and is rapidly absorbed from the GI tract but presence of food reduces its absorption; it is distributed widely throughout the body and gets metabolized in liver. The active deacetylated form is excreted in bile and undergoes enterohepatic recycling. The rest of the drug is excreted in urine.

Uses

  • 1.

    Tuberculosis: Rifampin is used along with INH and other antitubercular drugs for the treatment of TB. It is also used for chemoprophylaxis of tuberculosis.

  • 2.

    Leprosy (see p. 420).

  • 3.

    Prophylaxis of meningococcal and H. influenzae meningitis: Rifampin reaches high concentration in the nasopharynx and eradicates the carrier state in case of meningococcal and H. influenzae infections. It is given orally 600 mg every 12 hours for four doses in adults. In children, the dose of rifampin is 10 mg/kg every 12 hours for four doses.

  • 4.

    Rifampin, in combination with β-lactam antibiotics, may be useful in staphylococcal infections, such as endocarditis and osteomyelitis.

  • 5.

    Rifampin is used with doxycycline for the treatment of brucellosis.

Adverse effects and drug interactions

  • 1.

    Hepatitis is the main adverse effect – the risk of hepatotoxicity is more in alcoholics and elderly patients.

  • 2.

    Flu-like syndrome with fever, chills, headache, muscle and joint pain.

  • 3.

    GI disturbances, such as nausea, vomiting and abdominal discomfort.

  • 4.

    Skin rashes, itching and flushing.

It stains various body fluids, such as urine, tears, saliva, sweat and sputum, orange red, which is harmless.

Rifampin is a potent microsomal enzyme inducer, hence reduces the plasma levels of a number of drugs, such as oral contraceptives (resulting in contraceptive failure), oral anticoagulants, oral antidiabetic drugs, HIV PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). It also induces its own metabolism.

Pyrazinamide.

Pyrazinamide is a synthetic analogue of nicotinamide. It is active in acidic pH – effective against intracellular bacilli (has sterilizing activity). It has tuberculocidal activity. Like INH, pyrazinamide inhibits mycobacterial mycolic acid biosynthesis but by a different mechanism. It is given orally, absorbed well from the GI tract and distributed widely throughout the body including CSF. It is metabolized in liver and excreted in urine. The most important adverse effect of pyrazinamide is dose-dependent hepatotoxicity. It impairs the excretion of urates resulting in hyperuricaemia and may also precipitate acute attacks of gout in susceptible individuals. The other side effects are anorexia, nausea, vomiting, fever and skin rashes.

Ethambutol.

It is a first-line antitubercular drug. It inhibits arabinosyl transferases that are involved in mycobacterial cell wall synthesis. It is a bacteriostatic drug. It is used in combination with other antitubercular drugs to prevent emergence of resistance and for faster sputum conversion. There is no cross-resistance with other antitubercular drugs. Patients tolerate ethambutol well as it causes fewer adverse effects, and it is effective even in MAC infections.

Ethambutol is well absorbed after oral administration, is distributed widely in the body, is metabolized in liver, crosses BBB in meningitis and is excreted in urine. Optic neuritis is the main adverse effect seen with ethambutol, which is characterized by decreased visual acuity and colour vision defects (red–green). Hence, periodic eye examination is necessary when the patient is on ethambutol. The toxicity is reversible if the drug is discontinued early following onset of symptoms. It should be avoided in children younger than 6 years because they may not be able to report the disturbances in vision and it is also difficult to test visual acuity in children. Hyperuricaemia is due to decreased clearance of urates. Other side effects are nausea, vomiting, abdominal pain, skin rashes, itching and joint pain.

Streptomycin.

Streptomycin is an aminoglycoside antibiotic. It is a bactericidal drug. It is active against extracellular bacilli in alkaline pH. Streptomycin is not effective orally; it must be injected intramuscularly. The adverse effects are ototoxicity, nephrotoxicity and neuromuscular blockade.

Second-line antituberculosis agents

They are less effective, expensive and more toxic than the first-line drugs, hence are reserve drugs for TB.

Para-aminosalicylic acid.

It is structurally similar to sulphonamides. Like sulphonamides, PAS also competitively inhibits folate synthetase enzyme and prevents the formation of tetrahydrofolic acid (THFA) which is necessary for growth and multiplication of bacteria. Thus, PAS produces tuberculostatic effect. PAS is rapidly absorbed after oral administration and distributed widely all over the body, but poorly penetrates the BBB. It is metabolized in liver by acetylation and excreted in urine. PAS inhibits the acetylation of INH, thus increasing the plasma levels of INH. At present, PAS is a reserve drug for the management of MDR-TB. The common adverse effects are GI disturbances – anorexia, nausea, vomiting and abdominal discomfort – which can be minimized by giving the drug in divided doses on full stomach. The other side effects are hepatic damage, drug fever, skin rashes and thrombocytopenia.

Ethionamide.

It is structurally similar to INH but is less efficacious. It inhibits synthesis of mycolic acids. It is a bacteriostatic drug and is effective against both extracellular and intracellular bacilli. It is absorbed well after oral administration, and is distributed widely all over the body including CSF. It is metabolized in liver and excreted in urine. The common adverse effects are nausea, vomiting and epigastric pain. Other side effects are hepatitis, headache, blurred vision and paraesthesia.

Cycloserine.

It is a second-line antitubercular drug with bacteriostatic activity. It inhibits bacterial cell wall synthesis. It is distributed widely in the body including the CSF. The common side effects are related to CNS and include headache, tremor, psychosis and convulsions.

Terizidone.

The mechanism of action is similar to that of cycloserine. It is effective in both pulmonary and extrapulmonary TB. It achieves good concentration in urine, hence useful in TB affecting urinary tract. It is better tolerated than cycloserine.

Other antitubercular agents

  • Fluoroquinolones: Ciprofloxacin, ofloxacin, moxifloxacin and levofloxacin – bactericidal agents, given orally.

  • Aminoglycosides: Amikacin and kanamycin – bactericidal agents, administered parenterally. Amikacin is less toxic than kanamycin.

  • Capreomycin (i.m.) : May cause nephrotoxicity and ototoxicity.

  • Macrolides: Azithromycin and clarithromycin – given orally.

  • Rifamycins: Rifapentine and rifabutin – bactericidal agents, given orally.

    • Rifabutin: It is a derivative of rifampin. Rifabutin is preferred to rifampin for the treatment of TB in HIV-infected patients on PIs as rifabutin is a less potent enzyme inducer. It is also used for the treatment of MAC infection in combination with clarithromycin and ethambutol.

    • Rifapentine: Analogue of rifampin is a potent enzyme inducer.

  • Bedaquiline: It is a diarylquinoline. Bedaquiline inhibits production of energy in mycobacteria by inhibiting its ATP synthase. It is bactericidal and has a long half-life. It is administered orally. It is indicated for treatment of pulmonary MDR-TB in combination with other drugs. Bedaquiline should not be administered for more than 6 months. Patient should be monitored for response to treatment and adverse effects. It can cause hepatotoxicity and prolongation of QTc interval.

Treatment of tuberculosis PH1.55

The WHO recommends the use of MDT for all cases of TB. The objectives of MDT are as follows:

  • 1.

    To make the patient noninfectious as early as possible and decrease transmission of disease

  • 2.

    To prevent the development of drug-resistant bacilli

  • 3.

    To prevent relapse

  • 4.

    To reduce the total duration of effective therapy

The choice of standardized treatment regimens by each country – as recommended by the WHO – should be based on their efficacy, effectiveness and availability of financial resources.

All regimens for treatment of TB have two phases – an intensive phase followed by continuation phase.

  • 1.

    Intensive phase: The patient receives intensive treatment with four to six drugs daily for a period of 2 months. The main objective of this phase is to rapidly kill the bacilli and render the patient noncontagious.

  • 2.

    Continuation phase: The patient receives three to four drugs daily for a period of 4 months. This phase helps to eliminate the remaining bacilli and prevents relapse.

Guidelines for the treatment of tuberculosis

The regimen recommended for each patient depends on the diagnostic category for each patient. The Revised National Tuberculosis Control Programme (RNTCP) was launched in India in 1997. Under this programme, directly observed treatment, short-course (DOTS) treatment is being implemented. In DOTS, patient is administered drugs under the supervision of a health worker or other trained person to ensure that drugs are actually consumed. The therapy must be supervised and monitored by bacteriological examination. DOTS is the backbone of RNTCP. It is aimed at ensuring patient compliance, thus preventing the emergence of drug-resistant TB. The latest revision of RNTCP guidelines was in 2016.

Treatment of drug-sensitive tuberculosis ( table 11.16 )

They could be new or previously treated case.

  • New case: Those TB patients who have either never taken anti-TB drugs or taken them for less than a month.

  • Previously treated case: Those TB patients who have taken anti-TB drugs for 1 month or more. They include treatment of recurrent TB, loss to follow-up and treatment failure cases.

Table 11.16 ■
RNTCP 2016 guidelines for treatment regimens in drug-sensitive tuberculosis
Type of patient Intensive phase (IP) Continuation phase (CP)
New patients 2 HRZE 4 HRE 6
Previously treated patients 2 HRZES + 1 HRZE 5 HRE 8
The prefix number before a regimen indicates the number of months of treatment. H, isoniazid; R, rifampin; Z, pyrazinamide; E, ethambutol; S, streptomycin; RNTCP, Revised National Tuberculosis Control Programme.

For treatment of drug-sensitive TB, oral first-line drugs are administered daily as fixed-dose combinations, whereas streptomycin is injected i.m. as per body weight bands.

Dose of fixed dose combinations (FDCs) of first-line antituberculosis drugs and streptomycin for adults
( Source: Technical and Operational Guidelines for TB Control in India 2016 ( https://tbcindia.gov.in/showfile.php?lid=3219 ).)
Body weight (kg) Number of FDCs of HRZE a Number of FDCs of HRE b Streptomycin (g)
25–39 2 2 0.5
40–54 3 3 0.75
55–69 4 4 1
≥70 5 5 1
E, ethambutol; H, isoniazid; R, rifampin; Z, pyrazinamide.

a Taken during intensive phase; FDC of HRZE contains 75/150/400/275 mg, respectively.

b Taken during continuation phase; FDC of HRE contains 75/150/275 mg, respectively.

Drug resistance

( Source: Technical and Operational Guidelines for TB Control in India 2016 ( https://tbcindia.gov.in/showfile.php?lid=3219 ).)
Monoresistance The bacilli are resistant to only one first-line anti-TB drug
Polydrug resistance The bacilli are resistant to more than one first-line anti-TB drug but not both INH and rifampin
MDR The bacilli are resistant to both isoniazid and rifampin with or without resistance to any other first-line anti-TB drugs
XDR A MDR-TB case with bacilli being additionally resistant to a fluoroquinolone or second-line injectable anti-TB drug (amikacin, kanamycin/capreomycin)
INH, isonicotinic acid hydrazide; MDR, multidrug resistance; TB, tuberculosis; XDR, extensive drug resistance.

Multidrug-resistant tuberculosis PH1.45

MDR-TB can be treated by either standard or individualized regimens. Drug sensitivity testing should be done for all patients. Patients with or highly likely to have MDR-TB should be treated with regimens containing at least four drugs to which organisms are known or presumed to be susceptible. Pyridoxine should also be administered to patients with MDR-TB to prevent neurotoxicity due to ethionamide, cycloserine, etc.

Standard treatment regimen for MDR-TB
( Source: Technical and Operational Guidelines for TB Control in India 2016; https://tbcindia.gov.in/showfile.php?lid=3219 ).
Intensive phase (6–9 months) Continuation phase (18 months)
Kanamycin, levofloxacin, ethionamide, cycloserine, pyrazinamide, ethambutol + pyridoxine 100 mg/day Levofloxacin, ethionamide, ethambutol, cycloserine + pyridoxine 100 mg/day

All drugs are administered daily under directly observed treatment.

To address the problem of MDR-TB, DOTS plus has been implemented. It is recommended in areas where DOTS is fully in place.

Extensive drug-resistant tuberculosis (XDR-TB) PH1.45

Treatment is difficult and mortality rate is high.

Treatment of TB in HIV-positive patients

Generally, TB treatment is the same for HIV-infected as for non-HIV-infected TB patients. Short-course chemotherapy (daily regimen) must be started immediately once TB is diagnosed. Rifabutin is preferred to rifampin in HIV patients on antiretroviral drugs, such as PIs, as it does not interact with them.

Tuberculosis in pregnancy

All first-line drugs (INH, rifampin, pyrazinamide and ethambutol) except streptomycin can be used in pregnancy.

Management of antitubercular drug-induced adverse drug reactions (WHO guidelines)

  • Anorexia, nausea: Administer the drugs with small meals.

  • Burning/numbness in the extremities: Administer pyridoxine.

  • Joint pain (associated with pyrazinamide): Treat with NSAID.

  • Flu-like syndrome (with intermittent dosing of rifampin): Switch to daily administration of rifampin.

  • Jaundice/hepatitis: Major adverse effect associated with H, R and Z. All drugs have to be stopped till the reaction subsides. Then the drugs are reintroduced, one at a time. Rifampin is introduced first, followed by INH after 7 days. If both are tolerated, then Z should not be administered.

  • Skin rash: Stop anti-TB drugs. The drugs are restarted one at a time at low doses which is then gradually increased. If reaction occurs following reintroduction of a particular drug, it should be stopped.

  • Visual disturbances: Ethambutol should be discontinued.

Chemoprophylaxis of tuberculosis

It is the prophylactic use of antitubercular drugs to prevent the development of active TB in patients who are at risk. INH 300 mg (10 mg/kg in children) is administered daily for 6 months.

Indications for chemoprophylaxis

  • 1.

    Newborn of a mother with active TB

  • 2.

    Young children (younger than 6 years) with positive tuberculin test

  • 3.

    Household contacts of patients with TB

  • 4.

    Patients with positive tuberculin test with additional risk factors, such as diabetes mellitus, malignancy, silicosis and AIDS

Role of glucocorticoids in tuberculosis

TB is a relative contraindication for the use of glucocorticoids. However, in certain situations, glucocorticoids may be used under the cover of effective antitubercular therapy. They are as follows:

  • 1.

    TB of serous membranes like pleura, pericardium and meninges to prevent fibrous tissue formation and its sequelae

  • 2.

    To treat hypersensitivity reactions to antitubercular drugs

  • 3.

    TB of the eye, larynx and genitourinary tract to prevent fibrosis and scar tissue formation

Prednisolone is the preferred agent except in meningitis (dexamethasone is preferred as it lacks mineralocorticoid activity). When the patient’s general condition improves, the steroid should be gradually tapered to avoid HPA-axis suppression. Glucocorticoids are contraindicated in intestinal TB owing to the risk of perforation.

Drugs used in the treatment of mycobacterium avium complex infections

Clarithromycin/azithromycin, ethambutol, rifabutin. Other useful drugs are ciprofloxacin, levofloxacin and moxifloxacin. A combination of drugs is used. The duration of therapy required is 18–24 months. For prophylaxis, azithromycin/clarithromycin/rifabutin is used.

Antileprotic drugs PH1.46

Leprosy is a chronic infectious disease caused by M. leprae , which is an acid-fast bacillus.

Types of leprosy

Lepromatous leprosy

The cell-mediated immunity (CMI) is impaired against lepra bacilli ; hence, the course of the disease progresses very rapidly. This is characterized by extensive bilateral skin lesions which contain numerous lepra bacilli. There is involvement of more than one nerve.

Tuberculoid leprosy

The CMI is intact and is characterized by predominant peripheral nerve involvement with a single or few skin lesions. The bacilli are rarely seen in the lesions.

Plenty of lepra bacilli are seen in the skin lesions of borderline (BB), borderline lepromatous (BL) and lepromatous leprosy (LL); hence, these groups are called multibacillary leprosy (MBL).

Borderline tuberculoid (BT), tuberculoid (TT) and indeterminate (I) leprosy are referred to as PBL .

Drugs used for the treatment of leprosy.

Dapsone or diaminodiphenylsulphone (DDS), clofazimine, rifampin, ethionamide, ofloxacin, moxifloxacin, minocycline and clarithromycin are the drugs used in leprosy.

Dapsone or diaminodiphenylsulphone

Dapsone ( Fig. 11.11 ), a sulphone, is the oldest, cheapest and most widely used agent for the treatment of leprosy even today.

Fig. 11.11
Structure of dapsone.

Mechanism of action.

Sulphones are chemically related to sulphonamides and have the same mechanism of action. Lepra bacilli utilize PABA for the synthesis of folic acid, which, in turn, is necessary for its growth and multiplication. Dapsone is structurally similar to PABA, hence competitively inhibits folate synthetase enzyme and prevents the formation of THFA. Thus, dapsone produces leprostatic effect.

Pharmacokinetics.

Dapsone is given orally and is almost completely absorbed from the gut; it is bound to plasma proteins, widely distributed in the body and concentrated mainly in the infected skin, muscle, liver, kidney, etc. It is partly secreted in bile and undergoes enterohepatic cycling. Dapsone is metabolized by acetylation and metabolites are excreted in urine.

Adverse effects.

The common adverse effects are dose-related haemolytic anaemia particularly in patients with G6PD deficiency. Other side effects are anorexia, nausea, vomiting, fever, headache, allergic dermatitis, itching and peripheral neuropathy. Methaemoglobinaemia can also occur.

Dapsone may cause exacerbation of lesions – ‘sulphone syndrome’, which is characterized by fever, dermatitis, pruritus, lymphadenopathy, methaemoglobinaemia, anaemia and hepatitis.

Rifampin

It is the most effective and rapidly acting bactericidal drug for lepra bacilli. It kills most of the lepra bacilli.

Clofazimine

It is a phenazine dye and has leprostatic activity against lepra bacilli. It has anti-inflammatory effect, hence is also useful in the treatment of type 2 lepra reaction. Clofazimine binds to mycobacterial DNA to inhibit its template function. It also has activity against dapsone-resistant organism. It is given orally – fatty meal increases its absorption. It accumulates in tissues – t ½ is 70 days. It causes reddish-black discolouration of the skin on exposed parts. It can cause pigmentation of the conjunctiva and cornea, and discolouration of hair, tears, sweat, urine, etc. Nausea, vomiting, diarrhoea and abdominal pain are its other side effects. It is contraindicated in pregnancy.

Ethionamide

It is a second-line antitubercular drug and is also effective against lepra bacilli. Ethionamide can be used as an alternative drug when there is a contraindication for the use of clofazimine or if it is unacceptable. It may cause hepatotoxicity.

The other agents that are found to be effective against lepra bacilli are minocycline, clarithromycin, pefloxacin and ofloxacin.

  • Clarithromycin: It is a macrolide antibiotic and has bactericidal activity against M. leprae .

  • Minocycline: It is the only tetracycline that has antileprotic activity.

  • Ofloxacin: It has significant bactericidal activity against lepra bacilli.

  • Moxifloxacin: It has potent antileprotic activity.

Chemotherapy of leprosy

The WHO recommends the use of MDT for all leprosy cases. The National Leprosy Eradication Programme (NLEP) has implemented the guidelines for treatment. The objectives and need for MDT are as follows:

  • 1.

    To make the patient noncontagious as early as possible by killing the dividing bacilli

  • 2.

    To prevent the development of drug-resistant bacilli

  • 3.

    To prevent relapse

  • 4.

    To shorten the duration of effective therapy

Treatment schedules of leprosy PH1.55

All drugs are administered orally.

  • 1.

    For MBL (LL, BL and BB)

    • Rifampin 600 mg once monthly (supervised) +

    • Dapsone 100 mg daily (self-administered) +

    • Clofazimine 300 mg once monthly (supervised) +

    • Clofazimine 50 mg daily (self-administered)

      • The duration of treatment is 1 year.

  • 2.

    For PBL (TT, BT and I)

    • Rifampin 600 mg once monthly (supervised) +

    • Dapsone 100 mg daily (self-administered)

      • The duration of treatment is 6 months.

  • 3.

    Alternative regimens

    • Clofazimine + any two newer drugs (minocycline, ofloxacin, clarithromycin, etc.) daily for 6 months followed by clofazimine + ofloxacin/minocycline daily for another 18 months

If clofazimine cannot be used for MBL, then minocycline or ofloxacin is used.

Lepra reactions

These are immunologically mediated reactions that occur during the course of the disease. The exact cause of such reactions is not clear and is usually precipitated by infection, trauma, mental stress, etc. There are two types of reactions:

  • 1.

    Reversal reaction: It is a delayed type of hypersensitivity reaction seen in leprosy, both multibacillary and paucibacillary cases, e.g. BL and BT. There are signs of inflammation in the existing skin lesions – they become red, warm and swollen. New lesions may appear. Nerves are frequently affected. They are tender and painful. General symptoms are not common. They are treated with clofazimine or prednisolone.

  • 2.

    Erythema nodosum leprosum (ENL): It occurs in cases of LL. It is a type III hypersensitivity reaction (Arthus-type) due to release of antigen from the dying lepra bacilli. There is erythema nodosum – red, painful, tender cutaneous and subcutaneous nodules. Nerves may be affected. Constitutional symptoms are present. Severe form of reaction is treated with thalidomide, but pregnancy is the absolute contraindication for its use. The other drugs used are aspirin, clofazimine, chloroquine and prednisolone.

Antifungal agents

Most of the fungal infections ( Table 11.17 ) are opportunistic; hence they are common in diabetes mellitus, cancer, AIDS and pregnancy, and in patients on broad-spectrum AMAs and on immunosuppressant therapy such as prolonged course of corticosteroids and anticancer drugs.

Table 11.17 ■
Fungal infections/causative organisms
Superficial mycosis Deep mycosis
  • 1.

    Dermatophytes

  • 1.

    Aspergillus

  • (a)

    Epidermophyton

  • 2.

    Blastomyces

  • (b)

    Trichophyton

  • 3.

    Cryptococcus

  • (c)

    Microsporum

  • 4.

    Coccidioides

  • 2.

    Candida

  • 5.

    Candida

  • 3.

    Malassezia furfur

  • 6.

    Histoplasma

  • 7.

    Mucormycetes

  • 8.

    Sporothrix schenckii

Classification

  • 1.

    Polyene antibiotics: AMB, nystatin, hamycin

  • 2.

    Echinocandin antibiotics: Caspofungin acetate, micafungin

  • 3.

    Heterocyclic compound: Griseofulvin

  • 4.

    Azoles

    • (a)

      Imidazoles: Ketoconazole (KTZ), miconazole, clotrimazole, econazole, oxiconazole

    • (b)

      Triazoles: Fluconazole, itraconazole, voriconazole, posaconazole

  • 5.

    Allylamine: Terbinafine

  • 6.

    Antimetabolite: Flucytosine

  • 7.

    Other topical antifungal agents: Whitfield’s ointment, tolnaftate, sodium thiosulphate, selenium sulphide, undecylenic acid, ciclopirox, butenafine

Polyene antibiotics

AMB, nystatin and hamycin are polyene antibiotics; they have the same mechanism of action.

Amphotericin B.

AMB is a broad-spectrum antifungal antibiotic. It is effective against Cryptococcus , Coccidioides , Candida , Aspergillus , Blastomyces , Histoplasma , Sporothrix , fungi causing mucormycosis, etc.

Pharmacokinetics.

AMB is not absorbed from the gut, hence is not suitable orally for systemic infections. It is highly bound to plasma proteins and sterols in tissues, and widely distributed to various tissues but does not cross BBB. It is metabolized in liver and excreted slowly in urine and bile.

Mechanism of action.

Fungal cell membrane contains a sterol which resembles cholesterol and is called ‘ergosterol’.

Adverse effects.

AMB is the most toxic of all antifungal agents.

The acute reactions are fever, chills, headache, dyspnoea, GI disturbances, phlebitis at the site of injection, etc. The drug should be continued. Coadministration of steroid can minimize the reaction.

Anaemia and electrolyte disturbances are commonly seen. Anaemia is less with lipid-based formulations.

Nephrotoxicity with azotaemia is seen in most of the patients on AMB therapy. Hepatotoxicity can occur occasionally. Headache and convulsions may occur on intrathecal administration.

Formulations of amphotericin B.

AMB is poorly water soluble; hence, intravenous preparation is made with deoxycholate – conventional amphotericin B (C-AMB).

AMB colloidal dispersion (ABCD), AMB–lipid complex (ABLC) and liposomal AMB (L-AMB) are the lipid-based new formulations of AMB. L-AMB provides targeted drug delivery and has less adverse effects like acute reaction, anaemia and nephrotoxicity than conventional preparation. It is expensive.

Uses.

AMB is highly efficacious but highly toxic too; hence, azoles (fluconazole and itraconazole) have replaced AMB in the treatment of many fungal diseases.

  • 1.

    It is effective in almost all systemic mycoses, e.g. mucormycosis, aspergillosis, cryptococcosis, sporotrichosis, histoplasmosis and blastomycosis.

  • 2.

    It is useful topically for oral and cutaneous candidiasis.

  • 3.

    Other uses: L-AMB is useful in leishmaniasis (as the drug reaches the reticuloendothelial cells) and febrile neutropenia.

Nystatin.

Nystatin is poorly absorbed from skin and mucous membranes. It is highly toxic for systemic use. It is used only topically in Candida infections. It is available as suspension, ointment, cream, powder and tablet and also in combination with corticosteroids or antibacterial agents.

Uses.

Nystatin is used:

  • 1.

    Topically for oral, oropharyngeal, corneal, conjunctival and cutaneous candidiasis

  • 2.

    As oral tablets for intestinal candidiasis and superinfection due to Candida

  • 3.

    In vaginal candidiasis, as vaginal suppositories

Adverse effects.

They include nausea and bitter taste.

Hamycin.

It was developed in India (Hindustan Antibiotics)

It is useful topically for oral, cutaneous and vaginal candidiasis. It is available as ointment and suspension for topical administration.

Echinocandins

Caspofungin acetate.

C aspofungin a cetate is a semisynthetic antifungal agent effective against C andida and A spergillus . It is an antifungal antibiotic that acts by inhibiting the synthesis of glucans in fungal cell wall. It is not effective orally and is administered by i.v. infusion, metabolized in liver, and metabolites are excreted in faeces and urine. It is used in the treatment of invasive aspergillosis and candidiasis, when patient is not responding to or intolerant to other antifungal agents. The adverse effects include nausea, vomiting, flushing, fever and phlebitis at the site of injection. It is expensive.

Micafungin.

The mechanism of action is similar to that of caspofungin. It is administered for treatment of invasive candidiasis. It is also useful for prophylaxis of invasive candidiasis and in patients undergoing bone marrow transplantation.

Heterocyclic compound – griseofulvin.

Griseofulvin, an antifungal antibiotic, is used orally for dermatophytic infections. It is not effective topically.

Mechanism of action

Pharmacokinetics.

Griseofulvin is administered orally. Its bioavailability is increased by taking with fatty food and by using ultrafine preparation. It gets concentrated in keratinized tissues, such as skin, hair and nails. It is an enzyme inducer, thus reduces the effectiveness of warfarin and oral contraceptives. It may produce disulfiram-like action, hence can cause intolerance to alcohol. It is metabolized in liver and excreted in urine.

Uses.

Griseofulvin is used in the treatment of dermatophytic infections. The duration of treatment depends on the site of lesion and thickness of infected keratin layer. Treatment must be continued until infected tissue is completely replaced by normal skin, hair and nail. For tinea (ringworm) infections (tinea capitis, tinea barbae, tinea corporis, tinea pedis), 4–6 weeks of therapy is required. Ultrafine griseofulvin 250 mg q.i.d. for 4–6 weeks is given. In onychomycosis of fingernails, griseofulvin 250 mg q.i.d. for 6 months, and for toenails treatment up to 1 year, is required. Triazoles or terbinafine is preferred for onychomycosis.

Adverse effects.

They are headache, rashes, peripheral neuritis, confusion, fatigue, vertigo, blurred vision and GI effects, such as nausea, vomiting, diarrhoea and heartburn. The other side effects include leucopenia and rarely hepatotoxicity.

Antimetabolites

Flucytosine ( table 11.18 ).

Flucytosine is a prodrug. It is taken up by susceptible fungal cells and converted into 5-fluorouracil (5-FU) that interferes with fungal DNA synthesis by inhibiting thymidylate synthase enzyme, thus producing fungistatic effect.

Table 11.18 ■
Differences between amphotericin B and flucytosine
Amphotericin B Flucytosine
Active drug Prodrug
Has broad spectrum of activity Has narrow spectrum of activity
Antifungal antibiotic Antimetabolite
Fungicidal Fungistatic
Not absorbed through the GI tract Well absorbed from the GI tract
Highly bound to plasma proteins and sterols in tissues Poorly bound to plasma proteins
Does not cross BBB Freely crosses BBB and reaches high concentration in CSF
Metabolized in liver and excreted slowly in urine and bile Excreted in urine mainly in unchanged form
Highly efficacious and highly toxic drug Less effective and less toxic than AMB
Given intravenously, intrathecally and topically Given orally
AMB, amphotericin B; BBB, blood–brain barrier; CSF, cerebrospinal fluid; GI, gastrointestinal.

Flucytosine has narrow spectrum of activity and is effective against Cryptococcus , Chromoblastomyces and Candida spp.

Uses.

Flucytosine is used in combination with AMB for cryptococcal meningitis. The advantages of this combination are as follows:

  • 1.

    The entry of flucytosine into the fungal cells is facilitated because of increased permeability of membrane due to the action of AMB.

  • 2.

    Reduced toxicity of AMB because of reduction in drug dosage.

  • 3.

    Produces rapid culture conversion (culture becomes negative).

  • 4.

    Reduced duration of therapy and less chance for emergence of resistance.

Adverse effects.

These include bone marrow suppression with anaemia, neutropenia and thrombocytopenia. The other side effects include nausea, vomiting, diarrhoea, alopecia, skin rashes, itching and rarely hepatitis.

Azoles

Azole antifungals are broadly divided into imidazoles and triazoles. Both of them are structurally related compounds, and have similar mechanism of action and antifungal spectrum ( Table 11.19 ).

Table 11.19 ■
Antifungal drugs and their spectrum of activity
AMB Flucytosine KTZ Fluconazole Itraconazole Voriconazole Nystatin hamycin (topical) Griseofulvin (oral) Terbinafine Caspofungin acetate
  • Aspergillosis

  • Blastomycosis

  • Candidiasis

  • Cryptococcosis

  • Coccidioidomycosis

  • Histoplasmosis

  • Mucormycosis

  • Sporotrichosis

  • Cryptococcosis

  • Candidiasis (some species)

  • Chromoblastomycosis

  • Candidiasis

  • Dermatophytosis

  • Cryptococcosis

  • Candidiasis

  • Coccidioidomycosis

  • Candidiasis

  • Dermatophytosis

  • Blastomycosis

  • Histoplasmosis

  • Coccidioidomycosis

  • Aspergillosis

  • Sporotrichosis

  • Aspergillosis

  • Candidiasis

Candidiasis only Dermatophytosis only
  • Candidiasis

  • Dermatophytosis

  • Candidiasis

  • Aspergillosis

AMB, amphotericin B; KTZ, ketoconazole.

Mechanism of action.

Azoles impair ergosterol synthesis by inhibiting 14α-demethylase enzyme ( Fig. 11.12 ).

Fig. 11.12
Mechanism of action of azoles and terbinafine. θ, inhibition.

Miconazole and clotrimazole.

They are used topically for dermatophytic and Candida infections. They are available as cream, gel, lotion, solution, spray, vaginal pessary, etc. Clotrimazole troche is also available.

Uses

  • 1.

    Dermatophytic infections: Both are useful topically for tinea pedis , tinea cruris , tinea corporis and tinea versicolor .

  • 2.

    Candida infections: They are used topically for the treatment of oral, pharyngeal, vulvovaginal and cutaneous candidiasis.

  • 3.

    Miconazole is also useful in otomycosis .

Adverse effects.

These are local irritation, itching or burning. Miconazole is safe for use during pregnancy.

Ketoconazole.

KTZ is a prototype drug among azoles. It is effective orally as well as topically for various fungal infections, such as candidiasis, dermatophytosis and deep mycosis ( Table 11.19 ). It is the most toxic among azoles, hence used commonly by topical route for Candida and dermatophytic infections. For most of the systemic mycosis, it has been replaced by triazoles.

Pharmacokinetics.

It is orally effective. Acidic environment favours the absorption of KTZ; hence, its bioavailability is reduced by drugs like H 2 -blockers, proton pump inhibitors or antacids. It is highly bound to plasma proteins, metabolized in liver extensively and excreted mainly in faeces.

Adverse effects.

KTZ is the most toxic among azoles, but it is less toxic than AMB. Anorexia, nausea and vomiting are the most common side effects. KTZ reduces adrenal cortical steroids, testosterone and oestrogen synthesis – thus causes gynaecomastia, oligospermia, loss of libido and impotence in males, and menstrual irregularities and amenorrhoea in females. The other side effects are hepatotoxicity, hypersensitivity reactions like skin rashes and rarely itching.

Drug interactions.

KTZ is an enzyme inhibitor and increases the effect of the following drugs by inhibiting their metabolism:.

  • 1.

    KTZ × Sulfonylureas Hypoglycaemia

  • 2.

    KTZ × Phenytoin Phenytoin toxicity

  • 3.

    KTZ × Cyclosporine Potentiates nephrotoxicity

  • 4.

    KTZ × Warfarin Increased risk of bleeding

  • 5.

    KTZ × Terfenadine Fatal ventricular arrhythmias

Uses

  • 1.

    Dermatophytosis: KTZ is used topically for tinea pedis , tinea cruris , tinea corporis and tinea versicolor .

  • 2.

    Candidiasis: KTZ is very toxic for systemic use; hence, it has been replaced by triazoles.

  • 3.

    Other uses include kala-azar, dermal leishmaniasis and Cushing syndrome.

Fluconazole.

It is a triazole. It is available for oral and i.v. administration as well as for topical use in the eye. It has a broad spectrum of antifungal activity ( Table 11.19 ). It is less toxic than KTZ.

Pharmacokinetics.

It is well absorbed from the GI tract and has high bioavailability. Food or gastric pH does not affect its bioavailability. It is poorly bound to plasma proteins, widely distributed in the body, freely crosses the BBB and reaches high concentration in CSF. It is mainly excreted in urine in the unchanged form.

Adverse effects.

The common side effects are nausea, vomiting, diarrhoea and abdominal discomfort. The other side effects include headache, alopecia, skin rashes and hepatic necrosis. It is contraindicated during pregnancy because of teratogenic effect. Fluconazole is an enzyme inhibitor.

Uses

  • 1.

    Candidiasis : Fluconazole is effective against oesophageal, oropharyngeal, vulvovaginal, cutaneous and invasive candidiasis.

  • 2.

    Cryptococcal meningitis: Intravenous fluconazole is the preferred drug in the treatment of cryptococcal meningitis.

  • 3.

    In coccidioidal meningitis , i.v. fluconazole is the drug of choice.

It is not effective in aspergillosis.

Advantages over ketoconazole.

It does not inhibit steroid synthesis, does not have antiandrogenic effect, has less drug interactions and absorption is not affected by gastric pH.

Itraconazole.

It is a synthetic triazole. It is administered orally as well as by i.v. route. Gastric acidity favours the absorption of itraconazole. It is highly bound to plasma proteins, does not cross BBB and is metabolized in liver. It has a broad spectrum of activity against many fungi including Aspergillus .

Adverse effects.

These are nausea, vomiting, diarrhoea, headache, hepatotoxicity and hypokalaemia. Itraconazole inhibits CYP3A4 and can increase serum levels of drugs metabolized by this enzyme. Inhibition of steroid hormone synthesis is not seen with itraconazole.

Uses

  • 1.

    Intravenous itraconazole is the drug of choice for histoplasmosis, blastomycosis and sporotrichosis.

  • 2.

    Itraconazole is effective for oesophageal, oropharyngeal and vaginal candidiasis, but is not superior to fluconazole.

  • 3.

    Dermatophytosis: It is useful in tinea capitis , tinea corporis , tinea barbae and tinea versicolor .

  • 4.

    In onychomycosis, oral itraconazole is used.

  • 5.

    Unlike fluconazole, it is also effective in aspergillosis.

Voriconazole.

It is a triazole. It is used for the treatment of invasive aspergillosis and disseminated Candida infections. Voriconazole is administered orally or intravenously. Adverse effects of v oriconazole include v isual and auditory disturbances, prolongation of QT interval and skin rashes. It inhibits cytochrome enzymes. It is contraindicated in pregnancy.

Posaconazole.

Posaconazole, an azole, has a broad spectrum of activity against many fungi including Aspergillus and agents causing mucormycosis. It is administered orally; fatty food increases its bioavailability. Adverse effects include headache, sedation and GI disturbances.

Allylamine

Terbinafine.

Terbinafine, an allylamine, inhibits squalene 2,3-epoxidase and blocks ergosterol synthesis ( Fig. 11.12 ). It is available for topical as well as for oral administration ( Fig. 11.13 ). It is well absorbed after oral administration and is concentrated in skin, nails and adipose tissue. It is highly bound to plasma proteins, poorly penetrates the BBB, is metabolized in liver and is excreted in urine. It is effective against dermatophytes and Candida . Terbinafine is a fungicidal agent.

Fig. 11.13
Route of administration and spectrum of various antifungal agents. K, ketoconazole; M, miconazole; C, clotrimazole; F, fluconazole; I, itraconazole; T, terbinafine. KMC FI, have a wide spectrum of activity; terbinafine, for dermatophytes and Candida .

Adverse effects.

Terbinafine may cause side effects, such as nausea, diarrhoea, dyspepsia and rarely hepatitis. It may cause itching, rashes, local irritation on topical use.

Uses

  • 1.

    Dermatophytosis: Terbinafine is very effective against dermatophytes. It is used topically or orally for tinea pedis , tinea corporis and tinea cruris .

    • In onychomycosis of hands and feet, it is used orally and is more effective than itraconazole.

  • 2.

    Candidiasis: Terbinafine is less effective in Candida infections.

Other topical agents

  • 1.

    Whitfield’s ointment: It contains 6% benzoic acid and 3% salicylic acid. Salicylic acid has keratolytic and benzoic acid has fungistatic effects. It is used in the treatment of tinea pedis.

  • 2.

    Undecylenic acid: It is mainly a fungistatic drug. It is available as ointment, cream, powder, soap and liquid. It is used in the treatment of tinea pedis, tinea cruris and other dermatophytoses.

  • 3.

    Selenium sulphide: It is useful for tinea versicolor.

  • 4.

    Tolnaftate: It is useful in tinea cruris and tinea corporis.

  • 5.

    Ciclopirox: It is useful against tinea versicolor.

  • 6.

    Butenafine: Its mechanism of action and spectrum of activity is similar to that of terbinafine.

Antiviral agents PH1.48

Classification

  • 1.

    Drugs used against herpetic infection (antiherpes agents) : Acyclovir, valacyclovir, famciclovir, ganciclovir, valgancicloir, cidofovir, foscarnet, idoxuridine and trifluridine

  • 2.

    Drugs used against HIV infection (antiretroviral agents)

    • (a)

      Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine, stavudine, lamivudine, didanosine, zalcitabine, abacavir, emtricitabine, tenofovir

    • (b)

      Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine, delavirdine, efavirenz

    • (c)

      Protease inhibitors (PIs): Saquinavir, indinavir, ritonavir, lopinavir, nelfinavir, amprenavir

    • (d)

      Fusion inhibitors: Enfuvirtide, maraviroc

    • (e)

      Integrase inhibitor: Raltegravir, dolutegravir

  • 3.

    Anti-influenza agents: Amantadine, rimantadine, oseltamivir, zanamivir, peramivir

  • 4.

    Other antiviral agents: Lamivudine, tenofovir, adefovir dipivoxil (anti–hepatitis B) and interferons, ribavirin, sofosbuvir (anti–hepatitis C)

Antiherpes agents

They are used for treatment of various herpetic infections.

Acyclovir.

It is a synthetic, purine nucleoside analogue that has antiherpes activity. It is more effective against HSV-1 and HSV-2 than varicella zoster virus (VZV) infections.

Mechanism of action

Acyclovir is selectively taken up by herpes virus–infected cells and activated to triphosphate derivative which inhibits viral DNA synthesis. It is available for oral, topical and i.v. administration. It is a highly potent antiherpes drug. It has high therapeutic index with low toxicity to host cells.

Its oral bioavailability is poor. It is poorly bound to plasma proteins, widely distributed in the body, freely crosses BBB and is excreted in urine.

Uses

  • 1.

    Genital herpes: Oral/intravenous/topical acyclovir is effective in genital herpes simplex infections. It is used for primary and recurrent infections; high doses of acyclovir are needed for recurrent infections. It reduces the frequency and severity of herpetic lesions.

  • 2.

    Herpetic encephalitis: Intravenous acyclovir is the drug of choice for encephalitis caused by HSV.

  • 3.

    Herpes simplex keratitis: Acyclovir is used topically in herpetic keratoconjunctivitis.

  • 4.

    Mucocutaneous HSV: Acyclovir is used orally or topically in the treatment of stomatitis, herpes labialis and ulcers in mouth. It is used intravenously in immunocompromised patients.

  • 5.

    Herpetic whitlow (nail-bed infection): Oral acyclovir is useful for the prevention and treatment of whitlow.

  • 6.

    Chickenpox: Acyclovir reduces the duration of illness if started early in patients at risk of severe illness and immunocompromised individuals.

  • 7.

    Herpes zoster: Acyclovir (oral/topical/i.v.) and valacyclovir (oral) are effective.

Adverse effects.

Acyclovir is usually well tolerated. Nausea, vomiting, diarrhoea and headache are the other side effects. High doses may cause neurotoxicity with tremor, confusion, disorientation and convulsions. On topical use, it can cause irritation and burning.

Idoxuridine.

Idoxuridine is a thymidine analogue that acts against DNA viruses. It inhibits viral replication. Idoxuridine is used topically for HSV keratoconjunctivitis. The adverse effects are local irritation, itching, pain and swelling of lids.

Valganciclovir.

It is a prodrug of ganciclovir. It has better bioavailability than ganciclovir.

The important features of some of the antiherpetic agents are given in Table 11.20 .

Table 11.20 ■
Important features of the antiherpetic agents
Valacyclovir Famciclovir Ganciclovir Foscarnet Cidofovir
Active/Prodrug Prodrug Prodrug Active Active Prodrug
Route of administration and oral bioavailability Oral; better oral bioavailability than acyclovir Oral, well absorbed from the GI tract Intravenous, oral Intravenous Intravenous
Uses Genital herpes, orolabial herpes, herpes zoster Genital herpes, orolabial herpes, herpes zoster Prophylaxis and treatment of severe CMV infections – retinitis, pneumonia, gastroenteritis, etc., in immunocompromised patients Acyclovir resistant HSV and VZV infections CMV retinitis
Adverse effects Nausea, vomiting, skin rashes, CNS symptoms (in high doses) Nausea, vomiting, diarrhoea, headache Bone marrow suppression, nausea, vomiting, headache, hallucinations, convulsions, mutagenic, carcinogenic, embryotoxic Nephrotoxicity, convulsions, headache, hallucinations, anaemia Nausea, vomiting, hypersensitivity, nephrotoxicity, mutagenic, embryotoxic
CNS, central nervous system; GI, gastrointestinal; VZV, varicella zoster virus.

Anti-influenza agents

Amantadine.

It is an antiviral drug that has antiparkinsonian effect as well. It inhibits the uncoating and assembly of influenza A virus, thus prevents viral replication. It is administered orally, well absorbed from the GI tract and excreted unchanged in urine.

Uses

  • 1.

    Amantadine is used for the prophylaxis and treatment of influenza A virus infection.

  • 2.

    For parkinsonism.

Adverse effects.

They include anorexia, nausea, epigastric discomfort, headache, insomnia, confusion, hallucinations and hypotension. It is contraindicated in pregnancy because of teratogenic effect.

Rimantadine.

Its mechanism of action is similar to that of amantadine, but has a longer duration of action. It is administered orally, well absorbed through the GI tract, extensively metabolized and excreted in urine.

Oseltamivir.

It selectively inhibits influenza A and B virus neuraminidases, thus interfering with the release of virus from infected cells. It is used orally in the treatment and prevention of influenza A (avian influenza or bird flu and swine flu) and influenza B virus infections. Adverse effects are nausea, vomiting and abdominal discomfort. Dose: for prophylaxis, 75 mg o.d. for 7 days; for treatment, 75 mg b.d. for 5 days.

Zanamivir.

The mechanism of action and uses are similar to those of oseltamivir. Oral bioavailability is low. It is administered by inhalation. Adverse effects are bronchospasm, headache and dizziness. It should be avoided in patients with airway disease.

Peramivir.

It is active against influenza A and B, bird flu and swine flu virus. It is administered as a single i.v. dose in severe influenza. It is well tolerated.

Anti-hepatitis drugs PH1.48

Anti–hepatitis B drugs

The aim of treatment is viral suppression and prevention of complications like cirrhosis. Lamivudine, tenofovir, entecavir and adefovir dipivoxil inhibit hepatitis B virus DNA polymerase. Tenofovir is well tolerated and highly effective for chronic hepatitis B virus infections.

Anti–hepatitis C drugs

Treatment is directed to suppress the virus. Drugs are expensive. They include ribavirin (inhibits RNA synthesis), sofosbuvir (inhibits viral RNA polymerase), interferon (inhibits viral protein synthesis), daclatasvir and ledipasvir (inhibit HCV replication).

Interferons.

Interferons are proteins produced by virus-infected cells and also by recombinant DNA technology. There are mainly three types of interferons, namely α, β and γ. Antiviral activity of interferons is due to the inhibition of viral penetration, synthesis of mRNA, translation of viral proteins, assembly of viral particles and their release. They are administered by i.m. and s.c. routes or locally into the lesion.

Uses.

Interferon-α is used for the treatment of venereal warts, herpetic infections in immunosuppressed individuals, chronic hepatitis B and C and Kaposi sarcoma in HIV patients.

Adverse effects.

These include fever, headache, myalgia, skin rashes, alopecia, bone marrow suppression, cardiotoxicity, neurotoxicity and thyroid dysfunction.

Ribavirin.

It is a synthetic purine nucleoside analogue and has a wide range of antiviral activity. Ribavirin monophosphate competitively inhibits cellular enzymes that are needed for the synthesis of guanosine triphosphate (GTP) and nucleic acid. Ribavirin triphosphate also competitively inhibits the viral mRNA synthesis. It is administered by oral, aerosol or i.v. routes. It is metabolized in liver and excreted in urine.

Ribavirin is effective against a wide range of RNA and DNA viruses. It is used to treat influenza, parainfluenza, measles, adenovirus and respiratory syncytial virus infections. Oral ribavirin is effective in the treatment of chronic hepatitis C infection.

Adverse effects.

These include nausea, tiredness, cough, dyspnoea, anaemia and insomnia. Conjunctival and respiratory irritation may occur on aerosol therapy. Ribavirin is contraindicated in pregnancy and child-bearing age group because of its teratogenic, mutagenic, embryotoxic and gonadotoxic effects.

Antiretroviral drugs PH1.48

Classification of antiretroviral drugs is shown on p. 430. NRTIs, PIs and integrase inhibitors are effective against both HIV-1 and HIV-2. NNRTIs and entry inhibitors are active against HIV-1.

Nucleoside reverse transcriptase inhibitors

These drugs, after entering HIV-infected cells, are converted to their active triphosphate forms by cellular kinases and competitively inhibit HIV reverse transcriptase. They get incorporated into the growing viral DNA and cause termination of chain elongation of proviral DNA ( Fig. 11.14 ).

Fig. 11.14
Steps in the life cycle of HIV with sites of action of antiretroviral drugs. TP, triphosphate.

Zidovudine (azidothymidine [AZT]).

Zidovudine, a thymidine analogue, was the first antiretroviral drug approved for the treatment of HIV infection. It is the prototype drug of NRTIs. Zidovudine is effective against HIV-1 and HIV-2. It protects the uninfected cells from HIV, but has no effect on HIV-infected cells. Zidovudine is orally effective. It is well absorbed from the GI tract, metabolized in liver by glucuronide conjugation and excreted in urine. It crosses placental and BBB and is also secreted in milk.

Adverse effects and drug interactions.

Bone marrow suppression, anaemia and neutropenia are the common side effects. Nausea, vomiting, abdominal discomfort, headache and insomnia are commonly seen during the initial stages of therapy. Long-term therapy may cause hepatotoxicity, myopathy with fatigue and lactic acidosis.

  • 1.

    Zidovudine × paracetamol: Both are metabolized by glucuronide conjugation. Paracetamol competes and interferes with glucuronide conjugation of zidovudine. This leads to a rise in the plasma concentration of zidovudine and its toxicity.

  • 2.

    Azoles × zidovudine: Azole antifungal agents are hepatic microsomal enzyme inhibitors. They inhibit the metabolism of zidovudine. This leads to an increase in plasma concentration of zidovudine resulting in its toxicity.

  • 3.

    Zidovudine and stavudine: They should not be combined together because they compete for intracellular phosphorylation.

Zidovudine is used in combination with other antiretroviral drugs for the treatment of HIV-infected patients. It is also used for postexposure prophylaxis (PEP) and to prevent vertical transmission of HIV.

Didanosine, stavudine, zalcitabine, lamivudine, emtricitabine and abacavir.

They are effective orally. Lamivudine is a commonly used agent in antiretroviral therapy (ART) because of its low toxicity and efficacy. Emtricitabine is one of the least toxic antiretroviral agents. Stavudine and didanosine should not be combined because of increased risk of peripheral neuritis, pancreatitis and lactic acidosis. Abacavir can cause hypersensitivity reactions.

Tenofovir (nucleotide reverse transcriptase inhibitor).

It is a nucleotide analogue of adenosine. It undergoes intracellular phosphorylation and inhibits viral reverse transcriptase enzyme resulting in termination of chain elongation of HIV DNA. Flatulence can occur with tenofovir. It should be cautiously used in patients with renal disease. It is used in combination with other antiretroviral agents for the treatment of AIDS. Tenofovir and lamivudine are also effective against hepatitis B virus.

Non-nucleoside reverse transcriptase inhibitors

NNRTIs are highly active against HIV-1 but have no effect on HIV-2. They directly and noncompetitively inhibit HIV reverse transcriptase enzyme. There is no cross-resistance with the NRTIs. They are used in combination with NRTIs in the treatment of AIDS. Adverse effects are skin rashes, fever, nausea, pruritus and CNS disturbances like headache, confusion, insomnia, bad dreams and amnesia.

Nevirapine.

It is a highly lipid-soluble drug and is almost completely absorbed from the GI tract. It freely crosses the placental barrier and BBB. It is secreted in breast milk. Rashes are the frequent side effect of nevirapine. It can cause hepatotoxicity (risk is increased if the patient is also on antiTB drug, rifampin). It is extensively metabolized in liver and excreted mainly in urine.

Efavirenz.

Efavirenz has a long duration of action and is administered once daily. It is taken on empty stomach. It mainly causes CNS side effects like headache and dizziness. Rashes also occur with efavirenz.

Protease inhibitors

Examples are indinavir, nelfinavir, atazanavir, saquinavir, lopinavir, ritonavir, fosamprenavir and darunavir.

They competitively inhibit the HIV protease enzyme and prevent cleavage of viral polyproteins to the final functional, structural and enzymatic components of HIV → immature and noninfectious viral particles are produced and infection of other cells is prevented.

Cross-resistance is common among the PIs, but there is no cross-resistance with reverse transcriptase inhibitors. PIs are used orally with reverse transcriptase inhibitors in patients with AIDS. They are extensively metabolized in liver. Nausea, vomiting and diarrhoea are common side effects. They also produce skeletal muscle wasting, lipodystrophy, insulin resistance, diabetes, etc.

Indinavir.

Nephrolithiasis and hyperbilirubinaemia are also seen. Good hydration can reduce the incidence of nephrolithiasis.

Nelfinavir.

Diarrhoea is an important side effect.

Ritonavir.

Ritonavir inhibits CYP3A4 and causes a number of drug interactions. It inhibits both HIV-1 and HIV-2 proteases. Low-dose ritonavir is used in combination with other PIs (saquinavir, lopinavir, indinavir and atazanavir) – boosted PI regimen . Ritonavir inhibits metabolism of coadministered PIs (by inhibiting CYP3A4), increases their bioavailability and half-life → dose and frequency of administration of coadministered PIs is reduced (number of tablets of PI to be taken is reduced). Nelfinavir is not combined with ritonavir as it is metabolized by a different enzyme.

Entry or fusion inhibitors

Enfuvirtide and maraviroc.

Enfuvirtide prevents fusion of HIV-1 membrane with host cell membrane → blocks viral entry into the cell. It is administered subcutaneously. Injection-site reactions like pain and erythema are the important adverse effects. It is given as an add-on drug in patients who are not responding to ongoing ART. It does not exhibit cross-resistance with reverse transcriptase inhibitors and PIs.

Maraviroc is a CCR5 chemokine receptor antagonist → blocks binding of CCR5 – tropic strains of HIV to host cell. It is given orally. It is generally well tolerated. Adverse effects like cough, myalgia, arthralgia, diarrhoea and hepatotoxicity may occur.

Integrase inhibitors

Raltegravir and dolutegravir.

They inhibit integrase enzyme → prevent integration of viral DNA with host DNA. They are effective against both HIV-1 and HIV-2. Dolutegravir is better tolerated and is administered once daily. Myopathy can occur with raltegravir; dolutegravir can cause hepatotoxicity. There is a risk of neural tube defect with dolutegravir during its use in the first trimester. Hence, it should be avoided during periconception period. Rifampin induces metabolism of dolutegravir; hence, dose of dolutegravir must be doubled when coadministered with rifampin.

Treatment of HIV infection PH1.55

Retroviruses contain RNA-dependent DNA polymerase (reverse transcriptase) enzyme. They cause selective depletion of CD4 cells leading to a profound decrease in cell-mediated immunity. Hence, the infected person is prone to severe opportunistic infections, Kaposi sarcoma and lymphoid malignancies.

Objectives of antiretroviral therapy

  • 1.

    To suppress HIV replication and improve immune status of the patient

  • 2.

    To prevent the emergence of drug-resistant virus

  • 3.

    To prevent opportunistic infections

Principles of therapy.

ART regimen is used to achieve the above objectives. In ART regimen, drugs with different mechanism of action should be used so that they produce synergistic effect. Use of drug combinations also prevents development of resistance. It usually consists of a combination of two NRTIs with a NNRTI/integrase inhibitor/PI.

Criteria for anti-HIV treatment.

The National AIDS Control Organization (NACO) has adopted WHO 2016 guidelines for treatment of HIV infection. As per guidelines, ART should be started in all HIV-infected patients irrespective of CD4 count or clinical stage. Treatment is lifelong. A combination of antiretroviral drugs is used.

  • First-Line ART Regimen in Adults

  • Two NRTIs + one NNRTI/integrase inhibitor (INSTI)

  • The preferred regimen is the following:

  • Tenofovir (TDF) + lamivudine (3TC) + efavirenz (EFV)

  • Tenofovir (TDF) + emtricitabine (FTC) + efavirenz (EFV)

  • Tenofovir (TDF) + lamivudine (3TC)/emtricitabine (FTC) + dolutegravir (DTG) is another first-line regimen which can be used.

  • Alternate regimens

  • Zidovudine (AZT) + lamivudine (3TC) + efavirenz (EFV)

  • Zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP)

  • Tenofovir (TDF) + lamivudine (3TC)/emtricitabine (FTC) + nevirapine (NVP)

  • Fixed-dose combination once daily is preferred for initiation of treatment.

Monitoring of therapy.

Estimation of HIV viral load is preferred.

Second-Line ART Regimen in Adults

It should consist of 2NRTIs + boosted PI.

The NRTIs to be used are the following:

  • Zidovudine (AZT) + lamivudine (3TC), if the first-line regimen was tenofovir based

  • Tenofovir (TDF) + lamivudine (3TC), if the first-line regimen was zidovudine based

  • Boosted PI:

    • Atazanavir/ritonavir (ATV/r) or lopinavir/ritonavir (LPV/r) is preferred.

    • Alternative boosted PI is darunavir/ritonavir (DRV/r).

Pregnant women.

ART should be started in all pregnant women with HIV irrespective of CD4 count and WHO clinical stage. A combination of tenofovir (300 mg) + lamivudine (300 mg) + efavirenz (600 mg) is recommended in HIV-positive pregnant women. Treatment is lifelong.

Prophylaxis in infants.

Infants of women on ART should receive nevirapine daily for 6 weeks.

Prophylaxis of HIV infection

Pre-exposure prophylaxis (PrEP) is administration of antiretroviral drugs prior to exposure to HIV for preventing HIV infection. Those at high risk of HIV infection include heterosexual men, women, transgenders and i.v. drug abusers. A fixed-dose combination of tenofovir (300 mg) + emtricitabine (200 mg) daily is used.

Post-Exposure Prophylaxis (PEP). Use of antiretroviral drugs after exposure has occurred to prevent HIV infection is post-exposure prophylaxis. Individuals who have had exposure (e.g. sexual exposure, needle-prick injury, exposure to blood, breast milk, CSF, pleural, pericardial fluid) need PEP depending on the risk of HIV transmission and HIV status of the source. PEP should be initiated as early as possible, preferably within 72 hours of exposure.

Preferred regimen for adults and adolescents:

Tenofovir (300 mg) + emtricitabine (200 mg) + lopinavir/ritonavir (400/100 mg)orTenofovir (300 mg) + emtricitabine (200 mg) + atazanavir/ritonavir (300/100 mg)

The drugs should be administered for 28 days.

PEP is not required if exposure is to tears, urine or sweat, or source is HIV negative.

Art in adults with tuberculosis

All TB patients with HIV should receive ART. Treatment with anti-TB drugs is started first. This is followed by administration of ART within 8 weeks of start of treatment with anti-TB drugs.

Antimalarial drugs PH1.47

Malaria is a protozoal infection caused by genus Plasmodium and transmitted to humans by the infected female Anopheles mosquito. The species of malarial parasites are Plasmodium vivax , Plasmodium ovale , Plasmodium malariae , P. falciparum and Plasmodium knowlesi . The incidence of malaria is increasing due to the resistance of vectors to insecticides and drug-resistant parasites. In India, P. vivax and P. falciparum are common.

Classification

  • 1.

    Chemical classification

    • (a)

      4-Aminoquinolines: Chloroquine, amodiaquine, piperaquine

    • (b)

      8-Aminoquinolines: Primaquine, tafenoquine

    • (c)

      Quinoline methanol : Mefloquine

    • (d)

      Alkaloids : Quinine, quinidine

    • (e)

      Antifolates: Pyrimethamine, sulphadoxine, dapsone, proguanil

    • (f)

      Antibiotics: Doxycycline, clindamycin

    • (g)

      Hydroxynaphthoquinone: Atovaquone

    • (h)

      Artemisinins: Artemisinin, artemether, artesunate, arteether, arterolane, dihydroartemisinin

    • (i)

      Aryl alcohol: Lumefantrine

  • 2.

    Clinical classification

    • (a)

      This classification is based on the stage of the parasite they affect ( Table 11.21 and Fig. 11.15 ).

      • (i)

        Tissue schizontocidal agents: These act on primary (pre-erythrocytic) and latent (hypnozoites) tissue forms in the liver, e.g. primaquine, and are effective against both forms; atovaquone and proguanil act on primary form.

      • (ii)

        Blood schizontocidal agents: These act on erythrocytic stage of Plasmodium and, thereby, terminate the clinical attack.

        • Rapid acting and high-efficacy agents , e.g. chloroquine, artemisinin derivatives, quinine, mefloquine, atovaquone, amodiaquine and lumefantrine.

        • Slow-acting and low-efficacy agents , e.g. proguanil, pyrimethamine + sulphadoxine and clindamycin; used always in combination with rapid-acting agents.

      • (iii)

        Gametocidal agents : These kill gametocytes of plasmodia in blood, e.g. artemisinin and primaquine (active against all species); chloroquine and quinine ( vivax ). They reduce transmission to mosquitoes.

      Table 11.21 ■
      Antimalarial drugs effective against various stages of life cycle of malarial parasite
      Hepatic stages Blood stages
      Stages of malarial parasite P rimary tissue forms Latent tissue forms (hypnozoites) Asexual forms Sexual forms
      Drugs
      • Sulfadoxine


      +
      • Pyrimethamine


      • P roguanil/atovaquone

      • P rimaquine

      • Primaquine

      • Tafenoquine

      • Chloroquine

      • Mefloquine

      • Quinine

      • Artemisinins

      • Sulfadoxine + pyrimethamine

      • Proguanil/atovaquone

      • Antibiotics

      • Tafenoquine

      • Chloro quine

      • Quinine

      • Prima quine

      • Artemisinins

      • Quinghaosu

      Note: Points to remember
      • 1.

        None of the agents available are effective against sporozoites.

      • 2.

        Most of the antimalarials are effective against asexual blood stages except primaquine.

      • 3.

        Only primaquine and tafenoquine are effective against hypnozoites (latent tissue forms).

      • 4.

        All agents with ‘ quine ’ (prima quine , chloro quine and quinine ) are effective against gametocytes except mefloquine and tafe no quine.

      • 5.

        P rimaquine, p roguanil and p yrimethamine are effective against hepatic p rimary tissue forms.

      Fig. 11.15
      The life cycle of malarial parasite and the site of action of antimalarial drugs.

    • (b)

      Based on clinical indication for use (clinical utility)

      • (i)

        Drugs used for causal prophylaxis , i.e. pre-erythrocytic stage of Plasmodium in liver, e.g. proguanil and primaquine. Primaquine is effective against all species but not used due to its toxic potential. Proguanil is effective mainly for P. falciparum .

      • (ii)

        Drugs for suppressive prophylaxis : Suppress erythrocytic phase, thus clinical attack of malaria is prevented – clinical disease is not manifested, e.g. chloroquine, mefloquine and doxycycline.

      • (iii)

        Drugs used for clinical cure : These agents act on erythrocytic stages of malarial parasite to terminate the clinical attack. They are rapid-acting and slow-acting blood schizontocidal agents.

      • (iv)

        Drugs used to prevent relapse : These drugs act on the latent tissue forms (hypnozoites) of P. vivax and P. ovale which cause relapse, e.g. primaquine and tafenoquine .

        • Radical cure of P. vivax and P. ovale is achieved with the use of a blood schizontocidal agent along with primaquine which acts on latent tissue forms (hypnozoites) to prevent relapse.

      • (v)

        Drugs used to prevent the transmission of infection to Anopheles mosquito (gametocidal agents): Primaquine has gametocidal effect against all species of plasmodia that infect humans.

4-Aminoquinolines

Chloroquine.

Chloroquine is a 4-aminoquinoline. It is very effective and rapidly acting blood schizontocide against P. vivax , P. ovale , P. malariae , chloroquine-sensitive strains of P. falciparum and P. knowlesi . It has no activity against liver forms (pre-erythrocytic and hypnozoites).

Mechanism of action.

Chloroquine is a basic drug, which is taken up by the acidic food vacuoles of susceptible plasmodia and inhibits the conversion of haeme to haemozoin. The ‘drug–haeme’ complex is toxic and kills the parasite. Resistance to chloroquine is common with P. falciparum .

In the acidic vacuole of plasmodia:

Pharmacokinetics.

Chloroquine is commonly administered by oral route. It is well absorbed after oral and parenteral administration. It has strong affinity for melanin-containing tissues. It gets rapidly distributed to tissues (extensive tissue binding); therefore, to achieve an effective therapeutic plasma concentration, a loading dose is used during treatment of malaria. It gets concentrated in liver, spleen, kidney, lungs, skin, etc. Chloroquine is metabolized in the liver and slowly excreted in urine.

Adverse effects and contraindications.

Chloroquine in antimalarial doses may cause nausea, vomiting, skin rashes, itching, headache and visual disturbances. Parenteral administration can cause hypotension, confusion, cardiac arrhythmias, convulsions and even cardiac arrest. Prolonged administration in large doses, as in rheumatoid arthritis, may cause irreversible retinopathy and ototoxicity. It can also cause myopathy, cardiomyopathy, neuropathy and rarely psychiatric disturbances. Long-term therapy requires ophthalmological examination once in 3–6 months. It should be avoided in patients with epilepsy. It should not be given with mefloquine (can precipitate seizures). It is safe for use in pregnancy.

Uses

  • 1.

    Malaria

    • (a)

      Chloroquine is the drug of choice for the treatment of acute attack of malaria caused by P. vivax , P. ovale , P. malariae , chloroquine-sensitive P. falciparum and P. knowlesi ( Table 11.22 ). Fever resolves within 24–48 hours; blood smear becomes negative within 2–3 days.

      Table 11.22 ■
      Regimens for treatment of malaria PH1.55
      • 1.

        Treatment of uncomplicated malaria

        • (a)

          For acute attack of malaria due to P. vivax, P. ovale, P. malariae

          • Oral chloroquine is the drug of choice.

          • Chloroquine 600 mg base (10 mg/kg) stat, followed by

            • 600 mg base (10 mg/kg) – second day

            • 300 mg base (5 mg/kg) – third day

        • (b)

          For radical cure of P. vivax and P. ovale

          • Chloroquine (as above)

          • +

          • Primaquine 15 mg base orally, from day 4 daily for 14 days

          • (Primaquine destroys the hypnozoites in liver and prevents relapse in P. vivax and P. ovale infections)

        • (c)

          For acute attack of malaria due to P. falciparum

          • (i)

            ACT regimen + Primaquine (on Day 2), single dose 0.75 mg/kg body weight (for gametocidal action)

            • ACT regimens

            • Artesunate (4 mg/kg) 100 mg BD × 3 days

            • +

            • Sulphadoxine and Pyrimethamine (S/P) 1500 mg/75 mg as a single dose – day 1 (recommended in India except north eastern states)

            • Artemether + Lumefantrine (AL) − (FDC – 20 mg + 120 mg ) 4 tablets BD × 3 days (for those with body weight > 35 kg) -preferably administered with fatty meal to increase absorption (recommended in north eastern states)

      • Artesunate 100 mg BD × 3 days

      • +

      • Mefloquine 750 mg (15 mg/kg) – 2nd day

      • and 500 mg (10 mg/kg) – 3rd day

      • (Mefloquine is given in divided doses to minimize nausea and vomiting)

      • Artesunate 4 mg/kg/day + Amodiaquine 10 mg/kg/day OD × 3 days

        • (ii)

          Alternative to ACT regimens

      • Quinine sulphate 8 mg base/kg orally TDS for 7 days with either

      • Doxycycline or clindamycin

      • 2.

        For severe or complicated P. falciparum malaria (cerebral malaria)

        • Parenteral antimalarials should be administered for at least 24 hours once started

        • Then complete the treatment with full course of oral ACT once the patient is able to take orally

        • Artesunate:

        • Dose: 2.4 mg/kg at 0 hour (i.v./i.m.); repeat at 12 and 24 hours

        • Then, once a day till patient is able to take oral medication

        • If patient is able to take orally after 24 hours, switch over to full course of 3-day oral ACT a

        • Alternatives

        • Quinine dihydrochloride 600 mg (20 mg/kg) is diluted in 500 mL of 5% dextrose and infused intravenously slowly over 3–4 hours; 10 mg/kg is repeated as i.v. infusion over 4 hours every 8 hours till the patient can take orally. Then oral quinine sulphate 600 mg t.d.s. should be substituted to complete 1-week therapy along with doxycycline 100 mg o.d. × 7 days. Blood pressure, blood glucose and electrocardiogram (ECG) should be monitored during quinine therapy. Infusion rate should not exceed 5 mg salt/kg/h

        • Artemether

          • On admission – 3.2 mg/kg i.m.

          • Then once a day – 1.6 mg/kg i.m. till patient can take orally – then switch over to full course of 3-day oral ACT

        • α/β Arteether

          • 150 mg i.m. daily for 3 days; then switch over to 3-day oral ACT when the patient can take orally

          • a Oral ACT : see treatment of uncomplicated falciparum malaria. ACT containing mefloquine should be avoided in cerebral malaria because of risk of neuropsychiatric complications.

        • Supportive measures

        • Tepid sponging for fever

        • Sodium bicarbonate to correct acidosis

        • Intravenous diazepam to control convulsions

        • 10% dextrose to combat hypoglycaemia

        • Blood transfusion to correct anaemia

      ACT, artemisinin-based combination therapy.
      NVBDCP guidelines for diagnosis and treatment of malaria 2014

    • (b)

      For malaria due to P. vivax and P. ovale , primaquine is also administered in addition to chloroquine (for radical cure ).

    • (c)

      Chloroquine is a very effective chemoprophylactic agent for all types of malaria ( Table 11.23 ) except that caused by the resistant strains of P. falciparum .

      Table 11.23 ■
      Regimens for chemoprophylaxis of malaria
      • (a)

        For travel to areas with chloroquine-sensitive P. falciparum, P. vivax, P. malariae and P. ovale malaria

        • Chloroquine phosphate is given orally. Chloroquine phosphate 500 mg (chloroquine 300 mg base) once weekly; start 1 week before entering the endemic area; continue during the stay there, and for 4 weeks after leaving that area

      • (b)

        In areas with chloroquine-resistant P. falciparum malaria

        • Mefloquine 250 mg salt (228 mg base) orally, once weekly; start 1 week before entering the endemic area; continue once weekly there, and for 4 weeks after leaving that area

        • Or

        • Doxycycline 100 mg orally daily, start 1 day before entering the endemic area; continue daily during the stay there, and daily for 4 weeks after leaving that area. Doxycycline is contraindicated in pregnancy and in children

        • Or

        • Atovaquone 250 mg + proguanil 100 mg, fixed-dose combination tablet is available for oral administration. One tablet of FDC daily; start 1 day before entering the endemic area; continue daily during the stay there and daily for 1 week after leaving that area

      • (c)

        For terminal prophylaxis (for P. vivax and P. ovale malaria – to prevent relapse)

        • Primaquine 30 mg daily is started shortly before or after the person leaves the endemic area, and continued for 2 weeks

  • 2.

    Other uses are the following:

    • M alaria.

    • A moebiasis – hepatic, as it is highly concentrated in the liver.

    • L epra reaction – anti-inflammatory effect is useful.

    • R heumatoid arthritis – it scavenges-free radicals and stabilizes lysosomal membrane.

    • I nfectious mononucleosis.

    • A utoimmune disorder – discoid lupus erythematosus.

Note: Uses of chloroquine: Mnemonic – MALARIA .

  • Tablet chloroquine phosphate 500 mg = 300 mg chloroquine base

  • Tablet chloroquine phosphate 250 mg = 150 mg chloroquine base

Amodiaquine.

It is a congener of chloroquine. The mechanism of action is similar to that of chloroquine. It is an erythrocytic schizontocide used in combination with artesunate for the treatment of chloroquine-resistant falciparum malaria. It is not used for prophylaxis of malaria owing to its toxicities – agranulocytosis and hepatotoxicity.

Piperaquine.

It is structurally related to chloroquine. It acts on blood stages of parasite. It has a long duration of action. Piperaquine is approved for use in combination with dihydroartemisinin for treatment of chloroquine-resistant falciparum malaria. It is also used in combination with arterolane.

Alkaloids

Quinine and quinidine.

Cinchona bark contains several alkaloids, of which quinine and quinidine are important.

Mechanism of action.

It is similar to that of chloroquine.

Pharmacological effects

  • 1.

    Antimalarial actions: Quinine is a highly effective blood schizontocide against all the four species of plasmodia. It has gametocidal activity against P. vivax . It has no activity on hepatic forms (i.e. pre-erythrocytic and latent tissue forms).

  • 2.

    Other actions

    • (a)

      GIT: Being bitter, quinine reflexly increases gastric acid secretion.

    • (b)

      CVS: Quinine directly depresses the myocardium and can cause hypotension. But this effect may not be seen with oral antimalarial doses.

    • (c)

      Skeletal muscle: Quinine directly depresses the skeletal muscle contraction. Response to ACh is also diminished – symptoms of myasthenia gravis are exaggerated, while symptoms of myotonia congenita are relieved.

    • (d)

      CNS: In therapeutic doses, quinine often causes disturbances of hearing and vision. It also has mild analgesic and antipyretic effects.

  • 3.

    Local action: Quinine has local anaesthetic effect, but there is invariably an initial irritation. Orally, it causes GI irritation with nausea, vomiting and abdominal discomfort. Intramuscularly, it causes local pain and necrosis. Intravenously, it can cause thrombophlebitis.

Pharmacokinetics.

Quinine is readily absorbed from the gut or i.m. site, well distributed in the body, extensively metabolized in liver and excreted mainly in urine.

Adverse effects.

Quinine causes dose-dependent toxicities. They are cinchonism, hypoglycaemia and hypotension. Cinchonism comprises tinnitus, deafness, visual disturbances like blurred vision and colour defects, headache, nausea and vomiting. These symptoms are reversible on stoppage of therapy. Hypoglycaemia is common with i.v. quinine which is due to release of insulin – it is treated with intravenous glucose. Hypotension is also seen with intravenous administration of cinchona alkaloids. Quinine in large doses can cause hypotension, cardiac arrhythmias and A–V block. Quinidine is more cardiotoxic than quinine.

‘Blackwater fever’, a hypersensitivity reaction to quinine, is characterized by haemolysis, haemoglobinaemia and haemoglobinuria leading to renal failure.

Quinine/quinidine should not be used concurrently with mefloquine because of risk of serious cardiac toxicity. Quinine can be used in pregnancy.

Uses

  • 1.

    Malaria: Quinine is effective for treatment of acute attack of chloroquine-resistant P. falciparum malaria. Combination of clindamycin or tetracycline with quinine enhances the antimalarial efficacy of quinine. In severe malaria, quinine or quinidine is administered intravenously.

  • 2.

    Nocturnal leg cramps: Quinine may be effective in some cases.

Quinine is not used for chemoprophylaxis of malaria because of its toxicity.

Quinoline methanol

Mefloquine.

It is a synthetic quinoline methanol. Like quinine, it is a highly effective blood schizontocide and has no effect on hepatic forms, i.e. pre-erythrocytic stages and hypnozoites of P. vivax . It has no gametocidal activity.

Mechanism of action.

It is similar to that of chloroquine and quinine. It binds to heme and causes damage to membrane of Plasmodium.

Pharmacokinetics.

Mefloquine is administered orally and is not suitable for parenteral use because of its local irritant action. It is well absorbed, widely distributed, highly bound to plasma proteins, secreted in bile and undergoes extensive enterohepatic cycling. It is slowly excreted in the faeces with a terminal half-life of about 3 weeks.

Uses.

Mefloquine is used for prophylaxis of chloroquine-resistant P. falciparum and P. vivax malaria. It is used in combination with artesunate for the treatment of chloroquine-resistant P. falciparum malaria.

Adverse effects.

The common side effects include nausea, vomiting, diarrhoea and dizziness. Nausea and vomiting can be minimized by dividing the dose. Neuropsychiatric symptoms and seizures can occur. Mefloquine is contraindicated in patients with conduction defects, epilepsy and psychiatric disorders. It is safe for use in young children.

Antifolates

They are pyrimethamine, sulphadoxine, sulphones (dapsone) and proguanil. They are not used as single agents in malaria owing to rapid development of resistance.

Mechanism of action.

Plasmodia utilize PABA for the synthesis of folic acid which, in turn, is necessary for DNA synthesis. Sulphadoxine and dapsone inhibit folate synthetase, whereas pyrimethamine and proguanil inhibit DHF reductase enzyme of the parasite. Sulfadoxine has a long half-life like pyrimethamine. Combination of these drugs (pyrimethamine + sulphadoxine/dapsone) inhibits two successive steps ( sequential blockade ) in the folate pathway, acts faster and produces enhanced antimalarial action ( supra-additive effect ).

Pyrimethamine.

Pyrimethamine is a slow-acting blood schizontocide and has a greater affinity for plasmodial DHF reductase. The combination of pyrimethamine with sulphadoxine along with artesunate is used in the treatment of chloroquine-resistant P. falciparum malaria. Pyrimethamine–sulphadiazine combination is the treatment of choice for toxoplasmosis in immunocompromised patients.

Preparations

Pyrimethamine25mg+sulphadoxine500mgPyrimethamine25mg+dapsone100mg

Pyrimethamine is completely absorbed after oral administration, binds to plasma proteins, and accumulates in liver, kidney, lungs and spleen. It has a long plasma half-life (80–90 hours) and is excreted slowly in urine. Adverse effects are skin rashes, urticaria, megaloblastic anaemia and teratogenic effect.

Proguanil (chloroguanide).

Proguanil is a prodrug. It has a wide margin of safety. It is a slow-acting blood schizontocide for all the four species of plasmodia. It also has activity against primary hepatic stages of P. falciparum . It is absorbed slowly after oral administration, metabolized in liver and excreted in urine. It rarely causes side effects, such as nausea, vomiting, diarrhoea, abdominal pain, haematuria and skin rashes.

Hydroxynaphthoquinone

Atovaquone.

Atovaquone is a rapidly acting blood schizontocide and is also effective against liver stages (pre-erythrocytic forms) of P. falciparum . It is administered orally. It is highly bound to plasma proteins and excreted unchanged in faeces via bile.

Atovaquone is used with proguanil (Malarone) for prophylaxis of chloroquine-resistant P. falciparum malaria. It is also effective in the treatment of opportunistic infections with P. jiroveci and T. gondii in immunocompromised patients. The common adverse effects include nausea, vomiting, diarrhoea, abdominal pain, skin rashes and headache. It should be avoided in pregnant women.

8-Aminoquinoline

Primaquine.

It is a synthetic 8-aminoquinoline. It is effective against hepatic stages, i.e. primary and latent tissue forms of Plasmodia species that infect humans. It also has marked gametocidal activity but is ineffective against erythrocytic forms of malarial parasite. The exact mechanism of action of primaquine is unknown. It probably acts by generating reactive oxygen radicals and interfering with the mitochondrial electron transport in the parasite.

It is almost completely absorbed after oral administration, widely distributed, metabolized in liver and excreted slowly in urine.

Primaquine is used for radical cure and terminal prophylaxis of P. vivax and P. ovale as it has strong activity against hypnozoites. For terminal prophylaxis, primaquine 15 mg daily is started shortly before or after return from an endemic area. For radical cure of relapsing malaria ( P. vivax and P. ovale ), a 2-week course of primaquine is given concurrently with chloroquine or after the treatment of acute attack.

Adverse effects.

These include nausea, vomiting and epigastric distress – can be minimized by taking it with food. The important side effect with primaquine is haemolytic anaemia in people with G6PD deficiency. Methaemoglobinaemia can also occur with primaquine. Primaquine is contraindicated in pregnancy.

(Tablet primaquine phosphate 26 mg contains 15 mg base of primaquine base.)

Tafenoquine.

It is an 8-aminoquinoline. It is very effective against latent tissue forms (hypnozoites) of P. vivax , and also has blood schizontocidal activity. It has a longer duration of action ( t ½ is 15–19 days), hence used as a single-dose antirelapse agent. It can cause hemolysis in G6PD deficient individuals.

Artemisinin and its derivatives (qinghaosu compounds).

Artemisinin is derived from the plant Artemisia annua. The semisynthetic derivatives of artemisinin are dihydroartemisinin, artemether and artesunate. Another compound, arteether, was developed in India.

They are highly effective against erythrocytic stages of all plasmodia. They also have gametocidal action – reduce transmission of malarial parasite. They have no effect on hepatic stages of the parasite.

Mechanism of action

Pharmacokinetics

  • Dihydroartemisinin: Oral

  • Artesunate: Oral, i.m., i.v., rectal

  • Artemether: Oral, i.m.

  • Arteether: i.m.

Artesunate and artemether are metabolized to the active metabolite, dihydroartemisinin.

Artesunate can enhance its own metabolism (autoinduction). The half-life of dihydroartemisinin is about 2 hours. Arteether has a longer half-life.

Adverse effects.

They are generally well tolerated. Artemisinins can cause mild GI disturbances, neutropenia and prolongation of QT interval.

Arterolane.

It is a synthetic derivative of artemisinin which acts on erythrocytic stages of the parasite. It is potent and has a rapid onset and short duration of action. A combination of arterolane with piperaquine has been found to be effective and well tolerated for the treatment of P. falciparum malaria.

Uses of artemisinins.

Artemisinins are used in the treatment of uncomplicated chloroquine-resistant falciparum malaria and severe malaria.

Artemisinins have a short half-life and are not used for chemoprophylaxis. They should not be used as monotherapy because of risk of development of resistance. They are used in combination with other antimalarials – artemisinin-based combination therapy (ACT) . They are more potent, faster acting, better tolerated and affect various erythrocytic forms of the parasite as compared to chloroquine. The use of ACT improves treatment efficacy, provides faster clinical cure and rapid parasite clearance, and prevents recrudescence and development of resistance. Artemisinin derivatives (short t ½) can be combined with slowly eliminated antimalarials (long t ½), e.g. mefloquine, lumefantrine and amodiaquine, for the treatment of chloroquine-resistant falciparum malaria – duration of therapy is 3 days. Artemisinins rapidly kill 90%–95% of parasites; the remaining parasites are killed by the other drug.

Artemisinin derivatives can also be combined with doxycycline, tetracycline and clindamycin – duration of therapy is 7 days.

Recommended ACT regimens for treatment of uncomplicated P. falciparum malaria are shown in Table 11.22 .

Severe malaria: It is a medical emergency. Patient with severe P. falciparum malaria may present with one or more of the following features: impaired consciousness, convulsions, prostration, respiratory distress, circulatory collapse, shock, jaundice, pulmonary oedema, spontaneous bleeding, haemoglobinuria, hypoglycaemia, metabolic acidosis, renal failure and hyperparasitaemia. (For treatment, see Table 11.22 , p. 442).

The main aim of treatment is to prevent mortality. Treatment should be started as early as possible. Artesunate is preferred to quinine for treatment of severe malaria because:

  • Risk of death is lower.

  • It causes rapid parasite clearance.

  • It is safe and well tolerated.

  • It does not require cardiac monitoring.

  • It does not require rate-controlled infusion.

  • Risk of hypoglycaemia is lower.

  • No cross-resistance with other antimalarial agents.

Lumefantrine

It is active against erythrocytic stages of all species of malarial parasite. Fatty meal increases its absorption. It can cause GI disturbances. It does not significantly prolong QT interval. It is used in the treatment of P. falciparum malaria in combination with artemether.

Antibiotics

Tetracyclines and clindamycin.

Tetracycline, doxycycline and clindamycin are slow-acting blood schizontocides for all species of plasmodia that infect humans. They do not affect hepatic stages. They are used in combination with quinine or artesunate for the treatment of P. falciparum malaria. Doxycycline can also be used alone as a chemoprophylactic agent for MDR strains of malaria. Tetracyclines should not be used in pregnancy and young children (younger than 8 years); clindamycin can be used safely in such cases.

Treatment of malaria during pregnancy:

P vivax malaria is treated with chloroquine. For P falciparum malaria, quinine with clindamycin is administered in first trimester; ACT in 2 nd and 3 rd trimesters. Doxycycline and primaquine are contraindicated in pregnancy.

Treatment of mixed infection due to both P falciparum and P vivax:

It should be treated as P falciparum malaria with ACT regimen (except ACT regimen of artesunete + sulfadoxine-pyrimethamine as it is not effective against P vivax ). A 14 day course of primaquine is also added.

Antiamoebic drugs PH1.47

Amoebiasis is a protozoal infection caused by E. histolytica , which is transmitted through faeco-oral route.

Classification (according to their site of action)

  • 1.

    Luminal amoebicides: They are poorly absorbed after oral administration, hence attain high concentration in the bowel. They act on trophozoites in the gut lumen and kill them.

    • (a)

      Amides: Diloxanide furoate and nitazoxanide

    • (b)

      8-Hydroxyquinolines: Iodoquinol, iodochlorhydroxyquin

    • (c)

      Antibiotics: Tetracyclines, paromomycin

  • 2.

    Tissue amoebicides: They attain high concentration in blood and tissues following oral or parenteral administration.

    • (a)

      Nitroimidazoles: Metronidazole, tinidazole, secnidazole, ornidazole, satranidazole

    • (b)

      Alkaloids: Emetine, dehydroemetine (DHE)

    • (c)

      4-Aminoquinoline: Chloroquine

Among tissue amoebicides, nitroimidazoles and alkaloids are used for intestinal and extraintestinal amoebiasis. Chloroquine is used for extraintestinal amebiasis.

Nitroimidazoles

Metronidazole.

Metronidazole is a nitroimidazole derivative which is highly effective against most anaerobic bacteria and several protozoa, such as E. histolytica , Giardia lamblia and Trichomonas vaginalis . It helps in the extraction of guinea worm ( Dracunculus medinensis ).

Mechanism of action

In the presence of oxygen (aerobes), highly reactive nitro radical cannot be generated; hence, it is ineffective against aerobes .

Pharmacokinetics.

Metronidazole is available for oral, i.v. and topical administration. It is usually well absorbed in the small intestine after oral administration and poorly bound to plasma proteins. It diffuses well into the tissues including brain; therapeutic levels are achieved in various body fluids – saliva, semen, vaginal secretion, bile, breast milk and CSF. Metronidazole is metabolized in liver and the metabolites are excreted mainly in urine.

Adverse effects.

Adverse effects are rarely severe to necessitate the discontinuation of the drug.

  • 1.

    GIT: Anorexia, nausea, metallic taste, dry mouth, epigastric distress, abdominal cramps and occasionally vomiting.

  • 2.

    Allergic reactions: These include skin rashes, urticaria, itching and flushing.

  • 3.

    CNS: Dizziness, vertigo, confusion, irritability, headache, rarely convulsions and ataxia may occur. Polyneuropathy may occur on prolonged therapy.

  • 4.

    Disulfiram-like reaction (nausea, vomiting, abdominal cramps, headache, flushing, etc.) may occur if taken with alcohol; hence, the patient should be warned to avoid alcohol during treatment with metronidazole.

Teratogenic effect is seen in experimental animals; hence, metronidazole should be avoided in pregnant women.

Drug interactions

  • 1.

    Metronidazole potentiates the anticoagulant effect of warfarin and other oral coumarins by inhibiting their metabolism. There is prolongation of prothrombin time; hence, reduction of warfarin dose may be needed.

  • 2.

    Metronidazole may potentiate lithium toxicity by decreasing the renal clearance of lithium.

  • 1.

    Amoebiasis: Metronidazole (400–800 mg t.d.s. for 7–10 days) is the first-line agent for the treatment of both intestinal and extraintestinal amoebiasis except in asymptomatic carriers ( Table 11.24 ). As the metronidazole is almost completely absorbed in the small intestine, it is not effective as a luminal amebicide.

  • 2.

    Trichomonas vaginitis: Metronidazole (400 mg t.d.s. orally for 7 days) is the drug of choice. Both sexual partners should be treated simultaneously.

  • 3.

    Giardiasis: Metronidazole is very effective and is given orally (200 mg t.d.s. for 7 days).

  • 4.

    Anaerobic infections: Metronidazole is highly effective in most of the anaerobic infections – pelvic inflammatory disease, lung abscess, intra-abdominal infection, etc., caused by B. fragilis , Clostridium and other anaerobic organisms.

    • (a)

      In anaerobic brain abscess, metronidazole is often used in combination with a third-generation cephalosporin.

    • (b)

      In antibiotic-associated pseudomembranous colitis, metronidazole is effective. It is cheaper and less toxic than vancomycin.

    • (c)

      Vincent’s angina: Metronidazole is combined usually with amoxicillin for treatment of Vincent’s angina (ulcerative gingival infection produced by anaerobes).

    • (d)

      In the treatment of H. pylori infection, metronidazole is useful in combination with clarithromycin or amoxicillin and a proton pump inhibitor.

    • (e)

      It is used for prophylaxis of colorectal surgery.

  • 5.

    Others: It is used for treatment of bacterial vaginosis, extraction of guinea worm and Crohn’s disease. Other nitroimidazoles are shown in Table 11.25 .

    Table 11.25 ■
    Other nitroimidazoles with their important features
    Drug Route of administration Uses Advantages and other features
    • 1.

      Tinidazole

    • Oral, i.v. infusion

    • Amoebiasis: 2 g once daily orally for 3 days or 600 mg twice daily for a week

    • Trichomoniasis and giardiasis: 2 g stat or 600 mg once daily for a week

    • Anaerobic infections: It can be used for H. pylori infection and prophylaxis of colorectal surgery

    • Longer duration of action and better tolerability than metronidazole

    • 2.

      Secnidazole

    • Oral

    • Single oral dose of 2 g is effective in mild intestinal amoebiasis, giardiasis and trichomoniasis

    • Single-dose therapy in mild intestinal amebiasis

    • The spectrum, side effects and mechanism of action are similar to those of metronidazole

    • 3.

      Ornidazole

    • Oral and i.v. infusion

    • Oral

    • Amoebiasis

    • Trichomoniasis and giardiasis

    • Anaerobic infections

    • Longer duration of action and better tolerability than metronidazole

    • 4.

      Satranidazole

    • Oral

    • Amoebiasis

    • Trichomoniasis and giardiasis

    • Anaerobic infections

    • Satranidazole does not have interaction with alcohol (disulfiram-like reaction), better tolerability than metronidazole

Table 11.24 ■
Treatment of amoebiasis
  • I.

    For asymptomatic carriers (luminal amoebicide is used)

    • Diloxanide furoate or paromomycin or iodoquinol

    • Tab. diloxanide furoate 500 mg t.d.s. for 10 days

  • II.

    For intestinal amoebiasis (amoebic dysentery or diarrhoea)

    • Metronidazole/tinidazole + luminal agent

  • Tab. metronidazole 400 mg t.d.s.

  • +

  • Tab. diloxanide furoate 500 mg t.d.s.

  • for 7–10 days

  • III.

    For severe amoebic dysentery and extraintestinal amoebiasis

    • Similar to intestinal amoebiasis (metronidazole + luminal agent) or metronidazole 500 mg i.v. infusion q6h till patient can take oral therapy (total duration is 10 days)

  • IV.

    Hepatic amoebiasis

    • Similar to severe amoebic dysentery (metronidazole + luminal agent). Chloroquine may be used if patient is not responding to above therapy (Tab. chloroquine phosphate 500 mg b.d. for 2 days, later 500 mg o.d. for 3 weeks)

Emetine group

Emetine and dehydroemetine (DHE).

Emetine is an alkaloid and DHE is a semisynthetic derivative. They are irritants, bitter in taste and nauseating, hence cannot be administered orally. They are administered through i.m. route. They kill tissue trophozoites and have no effect on cysts. They are highly toxic and are used only when metronidazole is contraindicated or if the patient is not responding to metronidazole. DHE is less toxic than emetine, hence preferred to emetine. It is administered in a dose of 60 mg once daily for 5 days. The duration of treatment should not exceed 10 days.

Adverse effects (mnemonic: Emetine)

  • 1.

    E mesis (vomiting) – due to the stimulation of chemoreceptor trigger zone (CTZ).

  • 2.

    M uscle weakness and stiffness.

  • 3.

    E CG changes – T-wave inversion and prolongation of PR interval.

  • 4.

    T achycardia, hypotension and cardiac arrhythmias.

  • 5.

    I tching and skin rashes.

  • 6.

    N ausea.

  • 7.

    E czematoid lesions may occur at the injection site.

Note: Patient should be hospitalized and advised to take bed rest during DHE therapy.

4-Aminoquinoline

Chloroquine.

Chloroquine is effective in hepatic amebiasis. It is administered orally. It is completely absorbed from the upper GI tract and gets concentrated in liver. Chloroquine is not effective in intestinal amoebiasis because it attains low concentration in the gut wall and lumen. A luminal amoebicide has to be added to it when used for hepatic amoebiasis.

Amides

Diloxanide furoate.

Diloxanide furoate is a synthetic compound. The trophozoites in gut lumen which form cysts are killed by diloxanide furoate (luminal amoebicide). It is not effective against tissue trophozoites. After oral administration, diloxanide furoate in the gut is split into diloxanide and furoic acid. The diloxanide moiety is partly absorbed; the unabsorbed portion in the gut exerts antiamoebic activity. It is the drug of choice for asymptomatic amoebic carriers. In intestinal and extraintestinal amoebiasis, diloxanide furoate is given along with a tissue amoebicide for complete eradication of the organism (i.e. both trophozoites and cysts). Diloxanide furoate is administered in a dose of 500 mg t.d.s. for about 7–10 days. It is well tolerated and rarely causes side effects, such as flatulence, nausea and skin rashes.

Nitazoxanide.

Nitazoxanide is a luminal amoebicide. It is converted to active metabolite (tizoxanide). It is useful orally in amoebiasis and giardiasis. Adverse effects are headache and GI disturbances.

8-Hydroxyquinolines

Hydroxyquinolines were widely used as luminal amoebicides in the past for amoebiasis. They have been banned in various countries because of their toxicity, subacute myelo-optic neuropathy (SMON).

Antibiotics

Tetracyclines.

They are luminal amoebicides. The unabsorbed portion of older tetracyclines reaches colon and inhibits the bacterial flora, which are required for survival of E. histolytica .

Paromomycin.

Paromomycin, an aminoglycoside, is a luminal amoebicide. It is not absorbed from the GI tract following oral administration. It alters the intestinal flora. Adverse effects like nausea, vomiting and abdominal pain can occur. Oral paromomycin is safe for use in pregnancy. It is also useful in kala-azar.

Treatment of other protozoal infections PH1.47, PH1.55

Some of the protozoal infections with their clinical features, the preferred drug in those conditions with regimen and alternative drugs are mentioned in Table 11.26 .

Table 11.26 ■
Treatment of other protozoal infections
Disease and causative organism Clinical features Preferred drug, route and dose Alternative drugs
  • Giardiasis: Giardia lamblia

  • Diarrhoea and flatulence

  • Metronidazole oral 200 mg t.d.s. for 7 days

  • Tinidazole

  • Nitazoxanide

  • Furazolidone

  • Paromomycin

  • Trichomoniasis: Trichomonas vaginalis

  • Itching and frothy discharge from vagina

  • Metronidazole oral 400 mg t.d.s. for 7 days. Both sex partners should be treated simultaneously

  • Tinidazole

  • * Leishmaniasis:

    • (i)

      Visceral leishmaniasis (kala-azar): L. donovani

  • Fever, splenomegaly, hepatomegaly, lymphadenopathy, epistaxis and bleeding gums

  • • Liposomal Amphotericin B: single dose 10 mg/kg i.v. infusion• Inj paromomycin with miltefosine for 10 days

  • Miltefosine (oral) - 28 days

  • Amphotericin B deoxycholate

  • Sodium stibogluconate if organism is sensitive

  • (ii)

    Cutaneous leishmaniasis

  • Papule, ulcers, depressed scar especially on face and hands

  • Liposomal Amphotericin B: 5 mg/ kg/day i.v. infusion twice a week for 3 weeks (total dose 30 mg/kg)

  • Toxoplasmosis: T. gondii

  • Congenital – fever, jaundice, diarrhoea, cataract, glaucoma, pneumonitis, myocarditis, hepatosplenomegaly

  • Pyrimethamine and sulphadiazine + folinic acid orally

  • Clindamycin

  • Pyrimethamine + azithromycin/clarithromycin/atovaquone

  • Spiramycin (pregnancy)

  • African trypanosomiasis or sleeping sickness – Trypanosoma brucei

  • Fever, lymphadenopathy, splenomegaly – later involvement of CNS and classical symptoms of sleeping sickness

  • Suramin

  • Melarsoprol

  • Pentamidine

CNS, central nervous system.

* Treatment as per National kala azar elimination Program; WHO Technical Advisory board 2010.

Miltefosine (oral).

The exact mechanism of action in kala-azar is unknown. It interacts with lipids in the cell membrane of the parasite.

Sodium stibogluconate (i.m./i.v.).

It is a pentavalent antimonial compound. The mechanism of action in kala-azar is unknown. It is converted to a toxic compound which kills amastigotes within macrophages. Resistance has developed to this drug.

Pentamidine (i.v., i.m. and aerosol).

It probably acts by inhibiting various enzymes, DNA and RNA synthesis in Leishmania . It is also effective against P. jiroveci .

Anthelmintics PH1.47

Anthelmintics are drugs used in the treatment of infestation with helminths in the intestinal tract or tissues of the body ( Table 11.27 ). Anthelmintics that kill worms are called vermicides and those that help to expel the worms are called vermifuges .

Table 11.27 ■
Drugs for the treatment of helminthiasis
Infestation and parasite Drugs
  • 1.

    Nematodes

    • (a)

      Roundworm ( Ascaris lumbricoides )

    • (b)

      Hookworm ( Ancylostoma duodenale , Necator americanus )

    • (c)

      Pinworm ( Enterobius vermicularis )

    • (d)

      Whipworm ( Trichuris trichiura )

    • (e)

      Threadworm ( Strongyloides stercoralis )

    • (f)

      Mixed worm infestation

    • (g)

      Filariasis ( Wuchereria bancrofti, Brugia malayi ), onchocerciasis ( Onchocerca volvulus )

    • (h)

      Guinea worm ( Dracunculus medinensis )

  • Albendazole

  • Mebendazole

  • Pyrantel pamoate

  • Albendazole

  • Mebendazole

  • Oxantel pamoate

  • Ivermectin

  • Albendazole

  • Albendazole

  • Mebendazole

  • Pyrantel pamoate

  • Diethylcarbamazine (DEC) + albendazole

  • Ivermectin + albendazole

  • Metronidazole

  • 2.

    Trematodes

    • (a)

      Blood flukes (schistosomes)

    • (b)

      Intestinal flukes

    • (c)

      Liver flukes

    • (d)

      Lung flukes

  • Praziquantel

  • 3.

    Cestodes

    • (a)

      Taenia saginata (beef tapeworm)

    • (b)

      Taenia solium (pork tapeworm)

    • (c)

      Diphyllobothrium latum (fish tapeworm)

    • (d)

      Hymenolepis nana (dwarf tapeworm)

    • (e)

      Neurocysticercosis (caused by T. solium )

    • (f)

      Hydatid disease ( Echinococcus granulosus )

  • Praziquantel

  • Niclosamide

  • Albendazole

  • Praziquantel

  • Albendazole

  • Mebendazole

Drugs

  • M ebendazole

  • A lbendazole

  • N iclosamide

  • I vermectin

  • P yrantel pamoate

  • A lbendazole a

    Albendazole is highly active against many helminths, hence worth noting again.

  • L evamisole

  • P raziquantel

  • D iethylcarbamazine citrate

Note: Mnemonic – MANIPAL PD.

Mebendazole.

Mebendazole is a benzimidazole and has a broad spectrum of anthelmintic activity. It binds to β-tubulin and inhibits microtubule polymerization. It also blocks glucose transport into the parasite. As a result, intestinal parasites are immobilized or die slowly.

Pharmacokinetics.

Mebendazole is administered orally, poorly absorbed from the GI tract, highly bound to plasma proteins and metabolized in liver. Most of the oral dose is excreted in faeces.

Adverse effects.

Systemic toxicity of mebendazole is low because of its poor absorption. It is well tolerated and rarely causes GI side effects – anorexia, nausea, vomiting, diarrhoea and abdominal discomfort. Occasionally, it may cause skin rashes, itching, drug fever, etc. It is contraindicated in pregnancy and children younger than 1 year.

Uses.

Mebendazole is highly effective against intestinal nematodes – roundworm, hookworm, whipworm, pinworm and mixed worm infestations. It is more effective than albendazole in trichuriasis.

Dose and administration.

Mebendazole 100 mg orally b.d. for 3 days. It does not require fasting or purging, is well tolerated and is relatively cheap.

Albendazole.

It is also a benzimidazole and has a broad spectrum of anthelmintic activity. The mechanism of action is similar to that of mebendazole.

Pharmacokinetics.

Albendazole is given orally. It is erratically absorbed – fatty food increases its absorption; it is metabolized in liver. It produces an active metabolite, albendazole sulphoxide, which is widely distributed into various tissues including hydatid cyst. Hence, albendazole is preferred to mebendazole in the treatment of hydatid disease.

Adverse effects.

Albendazole is very well tolerated. The side effects are rare, but can cause nausea, vomiting, diarrhoea and epigastric distress. During long-term therapy, it may cause hepatic dysfunction, headache, dizziness, fever, weakness, loss of hair and neutropenia.

Dose and administration.

It can be taken as a single oral dose of 400 mg for adults and children older than 2 years, and as 200 mg single dose for children between 1 and 2 years of age. It is taken at any time of the day, does not require fasting or purging and side effects are rare.

Uses

  • 1.

    Nematodes: Albendazole is highly effective against intestinal nematodes – roundworm, hookworm, whipworm, pinworm and threadworm – and also in mixed worm infestations. It is more effective than mebendazole in trichinosis.

  • 2.

    Neurocysticercosis: Both albendazole and praziquantel are highly effective in neurocysticercosis. But albendazole is preferred to praziquantel because of the following reasons:

    • (a)

      It is cheaper.

    • (b)

      Duration of treatment is shorter.

    • (c)

      It reaches high concentration in brain and CSF.

    • (d)

      It is less toxic and better tolerated.

    • (e)

      Glucocorticoids increase plasma levels of albendazole sulphoxide but decrease plasma praziquantel levels.

      • High doses of glucocorticoids are usually given with albendazole or praziquantel to minimize the inflammatory reactions to dying parasites. Drug treatment is contraindicated in ocular cysticercosis – blindness can occur due to inflammatory reaction.

  • 3.

    Hydatid disease: In hydatid cyst, surgical resection is the treatment of choice, but albendazole is the drug of choice for medical therapy.

  • 4.

    Filariasis: Single dose of (400 mg) albendazole is given with diethylcarbamazine citrate (DEC) or ivermectin in the treatment of lymphatic filariasis. Albendazole has adjuvant value.

Albendazole is also effective in cutaneous larva migrans.

Thiabendazole.

A benzimidazole, thiabendazole has a broad spectrum of anthelmintic activity and is effective against most of the nematodes. The mechanism of action is similar to that of mebendazole and albendazole. It is rarely used because of high incidence of toxicity.

Piperazine.

It is effective against roundworm and pinworm. It causes flaccid paralysis of worms that are later expelled by peristaltic movements. It is partly absorbed and most of the drug is excreted unchanged in urine.

Adverse effects.

The adverse effects include nausea, vomiting, abdominal pain, skin rashes and dizziness. It occasionally produces convulsions and is contraindicated in patients with epilepsy. It is safe for use during pregnancy.

Levamisole.

It is effective against roundworm and hookworm infestations. It is an immunomodulator. It is also used as an adjunct in rheumatoid arthritis and cancer chemotherapy.

Pyrantel pamoate.

It is highly effective for the treatment of roundworm, pinworm and hookworm infestations. Oxantel pamoate is effective in trichuriasis.

Mechanism of action

Pharmacokinetics.

Pyrantel pamoate is given orally but absorbed poorly; about 80%–90% of oral dose is excreted in faeces.

Dose and administration.

It can be taken as a single oral dose of 11 mg/kg, does not require fasting or purging, is well tolerated and is relatively cheap.

Adverse effects.

These include nausea, vomiting, diarrhoea, headache, dizziness, skin rashes and fever. It is contraindicated in infants.

Diethylcarbamazine citrate.

Diethylcarbamazine is the most effective drug used in the treatment of filariasis and tropical eosinophilia caused by W. bancrofti and B. malayi . DEC is available as citrate salt. It acts mainly on microfilariae but the adult worms are killed slowly only on long-term treatment. DEC damages the microfilarial membrane structure so that they are destroyed by host defences.

Pharmacokinetics.

It is well absorbed from the GI tract, widely distributed in the body, metabolized in liver and excreted in urine. DEC is safe for use during pregnancy.

Adverse effects

  • 1.

    Drug-induced effects: These include anorexia, nausea, vomiting, headache and dizziness.

  • 2.

    Parasite-induced reactions: These are due to the release of proteins from dying parasites. In onchocerciasis , DEC produces a severe reaction, which is termed ‘Mazzotti’ reaction. It is characterized by severe itching, fever, skin rashes, nausea, vomiting, headache, joint pain, lymphadenitis, keratitis and uveitis. Hence, DEC is not recommended in onchocerciasis. In W. bancrofti , the reaction is usually mild. This can be minimized by administering H 1 -blockers. The reaction is treated with H 1 -blockers and glucocorticoids.

Uses

  • 1.

    Filariasis: Diethylcarbamazine is the drug of choice for the treatment of filariasis due to W. bancrofti and B. malayi . It is administered orally, 6 mg/kg/day in three divided doses for 3 weeks. (DEC 100 mg three times daily is taken after food for 3 weeks.) Addition of single dose of albendazole 400 mg to DEC produces sustained microfilaricidal effect.

    • Diethylcarbamazine (300 mg) with albendazole (400 mg) is used to reduce transmission of filariasis.

  • 2.

    Tropical eosinophilia: It is treated with DEC, 100 mg t.d.s. for 3 weeks. Antihistaminics and glucocorticoids may be required to control allergic reactions.

Ivermectin.

It is the drug of choice in onchocerciasis and strongyloidiasis. It is effective against microfilaria of W. bancrofti and B. malayi .

Mechanism of action

Pharmacokinetics.

It is given orally, rapidly absorbed, widely distributed to various tissues, metabolized in liver and excreted mainly in faeces.

Uses

  • 1.

    Ivermectin is the drug of choice for onchocerciasis. It kills microfilariae but has little effect on adult worms. It relieves pruritus and skin disease.

  • 2.

    It is also very effective in strongyloidiasis, ascariasis and cutaneous larva migrans.

  • 3.

    It is used orally in the treatment of scabies and pediculosis.

  • 4.

    It is useful for mass chemotherapy of filariasis as single annual dose along with albendazole.

Adverse effects.

They are itching, skin rashes, oedema, headache, fever, muscle and joint pain. It can cause ‘Mazzotti’ reaction during treatment of filariasis. It is contraindicated in pregnancy and children.

Praziquantel.

Praziquantel is effective in the treatment of trematodes and cestodes but not for nematodes.

Mechanism of action

Praziquantel ↑↑ influx of Ca 2+ into the tegument increased muscular contraction and spastic paralysis

At higher concentration damages tegument death of the parasite

Pharmacokinetics.

Praziquantel is readily absorbed after oral administration, undergoes extensive first-pass metabolism in liver, is highly bound to plasma proteins, crosses the BBB and is excreted mainly in urine.

Adverse effects.

The most common side effect is dizziness. Other side effects are nausea, vomiting, abdominal discomfort, headache, drowsiness, skin rashes, itching, muscle and joint pain.

Uses

  • 1.

    Schistosomiasis: Praziquantel is the drug of choice for all species of schistosomes. Praziquantel 40 mg/kg, single oral dose usually produces a high cure rate. It is well tolerated and reasonably cheap.

  • 2.

    Tapeworm infestation: A single oral dose of praziquantel gives a very high cure rate in all tapeworm infestations.

  • 3.

    Neurocysticercosis (see under ‘“Albendazole’”): It is an alternative agent for neurocysticercosis.

Praziquantel is contraindicated in pregnancy and ocular cysticercosis.

Niclosamide.

It is the second drug of choice for T. saginata , D. latum and H. nana . It is poorly absorbed from the GI tract. It inhibits oxidative phosphorylation in the mitochondria of the parasite and rapidly kills adult worms but not the ova. It is given orally in the form of chewable tablets.

Adverse effects.

Niclosamide produces few minor side effects. They are nausea, vomiting, diarrhoea, headache, skin rashes, itching and abdominal discomfort.

Anticancer drugs PH1.49

Cancer is a disease of cells characterized by P rogressive, P ersistent, P urposeless and uncontrolled P roliferation of tissues.

Both normal and cancerous cells must pass through the following phases of cell cycle ( Fig. 11.16 ):

  • 1.

    G 1 phase (presynthetic phase): Synthesis of enzymes and other cellular components needed for DNA synthesis.

  • 2.

    Synthetic phase (S phase): DNA synthesis takes place.

  • 3.

    G 2 phase (premitotic phase): Synthesis of cellular components for mitosis (proteins and RNA synthesis).

  • 4.

    Mitotic phase (M phase): Mitotic cell division takes place.

  • 5.

    G 0 phase (resting phase): Cells stop dividing temporarily or permanently.

Fig. 11.16
Cell cycle kinetics.

Classification of anticancer drugs

  • 1.

    Alkylating agents

    • (a)

      Nitrogen mustards: Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil

    • (b)

      Alkyl sulphonate: Busulphan

    • (c)

      Nitrosoureas: Carmustine, lomustine

    • (d)

      Triazene: Dacarbazine

  • 2.

    Platinum-containing compounds: Cisplatin, carboplatin, oxaliplatin.

  • 3.

    Antimetabolites

    • (a)

      Folate antagonist: Methotrexate

    • (b)

      Purine antagonists: 6-Mercaptopurine (6-MP), 6-thioguanine (6-TG), azathioprine

    • (c)

      Pyrimidine antagonists: 5-FU, cytarabine, capecitabine, gemcitabine.

  • 4.

    Vinca alkaloids: Vinblastine, vincristine

  • 5.

    Taxanes: Paclitaxel, docetaxel

  • 6.

    Epipodophyllotoxins: Etoposide, teniposide

  • 7.

    Camptothecins: Topotecan, irinotecan

  • 8.

    Antibiotics: Actinomycin D, bleomycin, mitomycin C, doxorubicin, daunorubicin

  • 9.

    Enzyme: l-Asparaginase

  • 10.

    Miscellaneous agents: Hydroxyurea, imatinib

  • 11.

    Hormones and antagonists

    • (a)

      Oestrogens: Ethinyl estradiol, fosfestrol

    • (b)

      Selective oestrogen receptor modulators (SERMs): Tamoxifen

    • (c)

      Selective oestrogen receptor downregulators (SERDs): Fulvestrant

    • (d)

      Aromatase inhibitors: Anastrozole, letrozole

    • (e)

      Progestins: Hydroxyprogesterone caproate, medroxyprogesterone acetate

    • (f)

      Antiandrogen: Flutamide

    • (g)

      5α-Reductase inhibitor: Finasteride

    • (h)

      GnRH analogues: Buserelin, goserelin, nafarelin

    • (i)

      Corticosteroids: Prednisolone and others

(Natural products: Vincristine, vinblastine, paclitaxel (from plants), doxorubicin, daunorubicin, mitomycin, L-asparginase from micro-organisms)

Toxicity of anticancer drugs (cytotoxic drugs)

While destroying cancer cells, anticancer drugs also affect rapidly proliferating normal cells. Bone marrow, skin, hair, GI mucosa, reticuloendothelial system, gonads, fetus, etc., are most severely affected.

  • 1.

    General toxicity

    • (a)

      Bone marrow suppression: It manifests as leucopenia, agranulocytosis, thrombocytopenia and aplastic anaemia. In such patients, infection and bleeding are common.

    • It is ameliorated/reduced by:

      • (i)

        Platelet transfusion

      • (ii)

        Granulocyte colony-stimulating factor (G-CSF)

      • (iii)

        Erythropoietin

      • (iv)

        Bone marrow transplantation

      • (v)

        Using bone marrow-sparing drugs if possible (e.g. l-asparaginase, bleomycin, cisplatin and vincristine)

    • (b)

      Immunosuppression: Decreased lymphocytes result in immunosuppression. Such patients are prone to opportunistic infections with fungi, bacteria, viruses and parasites ( P. jiroveci , Candida , cytomegalovirus, etc.).

    • (c)

      GIT: Nausea and vomiting are due to central action (stimulation of CTZ) and peripheral action in the GI tract. Most of the cytotoxic drugs cause vomiting. Cisplatin has the most emetogenic potential. 5-HT 3 antagonists, such as ondansetron and granisetron, are the commonly used antiemetics. The other antiemetics are metoclopramide and dexamethasone. Stomatitis, oral mucositis, diarrhoea, GI bleeding and ulcers are due to necrosis of rapidly dividing epithelial cells of gut mucosa.

    • (d)

      Skin and hair: Alopecia (loss of hair) is due to the damage to hair follicles. It is usually reversible on stoppage of therapy. Dermatitis and skin rashes too can occur.

    • (e)

      Gonads: Cytotoxic drugs also affect gonadal cells and cause oligozoospermia and infertility in males, and amenorrhoea and infertility in females.

    • (f)

      Fetus: Administration of cytotoxic drugs during pregnancy usually causes abortion or teratogenic effects.

    • (g)

      Hyperuricaemia: Gout and urate stones in the urinary tract are due to excessive cell destruction. They are prevented by good hydration, allopurinol and corticosteroids.

    • (h)

      Hypercalcaemia: It may be due to either the malignancy or certain anticancer drugs. It is treated with adequate hydration, bisphosphonates, corticosteroids, etc.

    • (i)

      Carcinogenicity (secondary malignancy) : These drugs may rarely cause secondary cancers in some patients, e.g. development of leukaemia in patients with prolonged use of alkylating agents.

    • (j)

      Mutagenicity .

  • 2.

    Specific toxicity

    • (a)

      Haemorrhagic cystitis with cyclophosphamide: Ameliorated by administering mesna systemically and acetylcysteine locally.

    • (b)

      Megaloblastic anaemia with methotrexate: Ameliorated by folinic acid/leucovorin/citrovorum factor.

    • (c)

      Nephrotoxicity with cisplatin: Saline infusion and mannitol reduce the incidence of nephrotoxicity.

    • (d)

      Neuropathy with vincristine and paclitaxel.

    • (e)

      Pulmonary fibrosis and pigmentation of skin with busulphan and bleomycin.

    • (f)

      Cardiotoxicity with doxorubicin and daunorubicin. An iron chelating agent, dexrazoxane, is useful in reducing the toxicity.

Alkylating agents

All alkylating agents have alkyl group(s) and are capable of introducing these groups into nucleophilic sites on DNA bases through the formation of covalent bonds. Alkylating agents are CCNS drugs. They also have radiomimetic effect.

Mechanism of action

  • Cross-linkage (inhibits DNA replication)

  • Abnormal base pairing (alkylated guanine base pairs with thymine rather than with cytosine and results in production of defective protein)

  • Break in the DNA strands

Cell death

Alkylating agents can also bind to proteins and damage them.

Nitrogen mustards

Cyclophosphamide.

Cyclophosphamide is a prodrug and is activated in liver ( Fig. 11.17 ). The final active metabolites derived from cyclophosphamide are phosphoramide mustard and acrolein. Phosphoramide mustard produces cytotoxic effect and acrolein is responsible for haemorrhagic cystitis.

Fig. 11.17
Cyclophosphamide and haemorrhagic cystitis.

Cyclophosphamide is administered orally or intravenously. The metabolites are excreted mainly in urine.

Adverse effects.

Cyclophosphamide can cause general toxicity (see p. 460). The specific toxicity of cyclophosphamide is severe haemorrhagic cystitis. It is associated with dysuria and haematuria due to irritation of bladder mucosa by acrolein. It is a dose-limiting toxicity and can be reduced by adequate hydration and coadministration of i.v. mesna (2-mercaptoethane sulphonate). Mesna is also excreted in urine where it binds and inactivates acrolein, thus prevents haemorrhagic cystitis.

Uses.

Cyclophosphamide is used in combination with other anticancer agents in the treatment of lymphomas, chronic lymphocytic leukaemia (CLL), breast cancer, etc. It also has a powerful immunosuppressant effect, hence is useful in rheumatoid arthritis, nephrotic syndrome and to prevent as well as to treat graft rejection during organ transplantation.

Ifosfamide is a congener of cyclophosphamide and is administered intravenously. It is useful in the treatment of testicular cancer and sarcomas.

Mechlorethamine.

It is one of the components of MOPP (nitrogen mustard, Oncovin, prednisone and procarbazine) regimen for Hodgkin disease. It is a highly irritant drug so care should be taken to avoid extravasation during i.v. administration.

Chlorambucil.

It is a slow-acting nitrogen mustard. Its main action is on lymphoid series and it produces marked lympholytic effect. It is given orally and was the standard treatment for CLL.

Melphalan.

It is highly effective in multiple myeloma and is used in combination with other agents.

Alkyl sulphonates

Busulphan.

It depresses bone marrow with selective action on myeloid series. It was the preferred drug for chronic myeloid leukaemia (CML). The common side effects are pigmentation of the skin, interstitial pulmonary fibrosis and hyperuricaemia.

Nitrosoureas

Carmustine and lomustine are highly lipid soluble drugs, hence reach high concentration in the CSF. Nitrosoureas are mainly used in brain tumours.

Procarbazine.

It is an alkylating agent. It damages DNA and is a component of MOPP regimen for Hodgkin disease.

Platinum-containing compounds

Cisplatin.

It is a heavy-metal complex with a highly effective antineoplastic activity. It is a CCNS drug and acts on both dividing and resting cells. Cisplatin is administered intravenously. It is highly bound to plasma proteins and gets concentrated in kidney, liver, intestine and testes. It poorly penetrates BBB and is slowly excreted in urine.

Mechanism of action.

Inside the cell:

Cisplatin is highly effective in the treatment of testicular, ovarian, endometrial and bladder cancer. It is also used in lung and oesophageal cancer.

Adverse effects.

Cisplatin is the most emetogenic anticancer drug. Nausea and vomiting can be controlled by 5-HT 3 antagonists, such as ondansetron or granisetron.

Nephrotoxicity: It can be minimized by proper hydration.

Ototoxicity with hearing loss can occur and is severe with repeated doses.

Electrolyte disturbances: Hypokalaemia, hypocalcaemia and hypomagnesaemia are common. Neuropathy is commonly seen with higher doses. Anaphylactic shock may rarely occur. Cisplatin has mutagenic, teratogenic and carcinogenic properties.

Carboplatin.

The mechanism of action is similar to that of cisplatin. It is better tolerated than cisplatin. It causes less nausea, ototoxicity and nephrotoxicity than cisplatin.

Oxaliplatin.

It is effective in colorectal and gastric cancer. Peripheral neuropathy is an important adverse effect.

Antimetabolites

Folate antagonist

Methotrexate.

MTX is one of the most commonly used anticancer drugs. It is a CCS drug and acts during S phase of the cell cycle. It has antineoplastic, immunosuppressant and anti-inflammatory effects.

Mechanism of action

MTX structurally resembles folic acid. It competitively inhibits dihydrofolate reductase enzyme and prevents the conversion of dihydrofolic acid (DHFA) to THFA, thus depletes the intracellular THFA. THFA is necessary for the synthesis of purines and thymidylate which, in turn, are necessary for DNA and RNA synthesis.

MTX is well absorbed after oral administration; it can also be given i.m., i.v. or intrathecally. It is bound to plasma proteins; it poorly crosses the BBB and most of the drug is excreted unchanged in urine.

MTX is the drug of choice for choriocarcinoma. It is also used in acute leukaemias, Burkitt lymphoma and breast cancer.

Low-dose MTX 7.5–25 mg once weekly is used for rheumatoid arthritis. It prevents joint erosion. It has anti-inflammatory and immunosuppressant effects. It is also used in psoriasis, inflammatory bowel disease and organ transplantation.

Adverse effects.

See general toxicity (p. 460). Other adverse effects are megaloblastic anaemia, pancytopaenia, hepatic fibrosis, etc.

Drug interactions.

Salicylates/sulphonamides/tetracyclines × MTX: These drugs displace MTX bound to plasma proteins and increase its free form in plasma leading to its toxicity.

NSAIDs and sulphonamides potentiate MTX toxicity by interfering with its excretion.

Folinic acid rescue/leucovorin rescue.

The toxic effects of MTX on normal cells can be minimized by giving folinic acid. Availability of folinic acid has helped the use of very high doses of MTX for a better antineoplastic effect. After a few hours of MTX therapy, leucovorin is given. Folinic acid is the active coenzyme form. It bypasses the block produced by MTX and rapidly reverses the toxicity. This method is called leucovorin rescue/folinic acid rescue.

Pemetrexed: It affects thymidylate synthase more than dihydrofolate reductase. Hand-foot syndrome can occur.

Purine antagonists: 6-Mercaptopurine and 6-Thioguanine

6-MP and 6-TG are activated to their ribonucleotides which inhibits purine ring biosynthesis and nucleotide interconversion. They are CCS drugs and act in S phase of cell cycle. 6-MP also has immunosuppressant action.

6-MP is administered orally and has poor penetration through BBB. It is metabolized by xanthine oxidase and its metabolite is excreted in urine.

Allopurinol interferes with the metabolism of 6-MP by inhibiting the enzyme xanthine oxidase and increases the antineoplastic effect of 6-MP. Therefore, allopurinol is frequently used in cancer patients receiving chemotherapy to prevent hyperuricaemia and to reduce the dose of 6-MP, thus reducing its toxicity. 6-MP is used mainly in acute lymphocytic leukaemia. Bone marrow depression is the major adverse effect of 6-MP.

Pyrimidine antagonists

Fluorouracil (5-FU).

5-FU is activated to fluorodeoxyuridine monophosphate (FdUMP) ( Fig. 11.18 ). This interferes with DNA synthesis and functions by inhibiting thymidylate synthetase enzyme.

Fig. 11.18
Mechanism of action of fluorouracil.

It is used in colorectal, upper GIT, breast and ovarian carcinomas.

Capecitabine.

It is a prodrug of 5-FU. It is useful in metastatic breast and colorectal cancer. Hand-foot syndrome is an important adverse effect.

Cytarabine.

It inhibits DNA synthesis. It is used in leukaemias and lymphoma.

Plant products

Vinca alkaloids.

Vinblastine and vincristine are derived from the periwinkle plant. They are CCS agents and act during M phase of cell cycle. Vinblastine and vincristine have the same mechanism of action but differ in antitumour spectrum and toxicity ( Table 11.28 ).

Table 11.28 ■
Uses and adverse effects of vinca alkaloids
Vinblastine Vincristine
  • Uses:

  • Hodgkin disease

  • Carcinoma of B reast

  • Testicular tumours

  • Uses:

  • C hildhood leukaemias

  • C hildhood tumours – Wilms tumour, neuroblastoma

  • Hodgkin disease

  • Toxicity:

  • B one marrow suppression, anorexia, nausea, vomiting and diarrhoea

  • Toxicity:

  • Peripheral neuritis with paraesthesia, constipation. Vincristine has minimal myelosuppressive action

Mechanism of action

Taxanes.

Paclitaxel is a taxane derived from the bark of the western yew tree. Docetaxel is a newer taxane.

Mechanism of action

Paclitaxel is administered by i.v. infusion. It is useful in advanced breast, ovarian, lung, oesophageal and bladder cancer. The unwanted effects are bone marrow suppression, peripheral neuropathy, myalgia and hypersensitivity reactions.

Camptothecins

Topotecan and irinotecan are camptothecin analogues.

Mechanism of action.

Camptothecins bind to and stabilize DNA–topoisomerase I complex and inhibit the resealing function (the strand-breaking action is not affected), thus producing cell death. They are used in advanced ovarian, lung and colorectal cancer. The common side effects are bone marrow suppression and GI disturbances.

Epipodophyllotoxins

They act in S–G 2 phases of cell cycle.

Mechanism of action

Etoposide is used in testicular and lung cancers in combination with other cytotoxic drugs. It is also effective in non-Hodgkin lymphoma and AIDS-related Kaposi sarcoma. The side effects are bone marrow suppression and GI side effects such as nausea, vomiting and diarrhoea. Hepatotoxicity is seen with high doses.

Anticancer antibiotics

Mechanism of action.

Anticancer antibiotics have a direct action on DNA. Dactinomycin, doxorubicin and daunorubicin bind to DNA through intercalation between adjoining nucleotide pairs on the same strand of DNA and block transcription of DNA. Bleomycin binds to DNA and produces free radicals which cause DNA damage.

Actinomycin D.

It is administered intravenously. It is mainly used in the treatment of Wilms tumour, Ewing sarcoma and choriocarcinoma. Bone marrow suppression and GI side effects are prominent.

Mitomycin C.

It is converted to a compound which acts as an alkylating agent. It is used in the treatment of GI tumours, cervix and bladder cancer. It produces mainly bone marrow suppression, GI side effects and nephrotoxicity.

Bleomycin.

It can be administered through s.c., i.m. and i.v. routes. It is used in the treatment of testicular and ovarian tumours and in Hodgkin lymphoma (ABVD *

* Adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine

regimen). Its main side effects are hyperpigmentation of the skin and pulmonary fibrosis. There is very little bone marrow suppression (spares bone marrow).

Doxorubicin and daunorubicin.

Daunorubicin is effective in acute leukaemias; doxorubicin is active against solid tumours. The side effects are bone marrow suppression, GI disturbances and cardiomyopathy with CCF, hypotension or arrhythmias.

Mithramycin.

It is an anticancer antibiotic that reduces serum calcium levels by inhibiting osteoclasts. It is used in the treatment of hypercalcaemia with bone metastasis.

Enzyme

L-Asparaginase.

It is an enzyme that is isolated from bacteria, E. coli . Asparagine is an amino acid which is necessary for protein synthesis. Normal cells can synthesize asparagine because they contain asparagine synthetase enzyme. Cancer cells lack this enzyme, so they depend on exogenous source – plasma.

L -Asparaginase degrades asparagine (in plasma) to aspartic acid. Hence, neoplastic cells are deprived of asparagine, resulting in cell death. It is used in the treatment of acute lymphoblastic leukaemia (ALL).

Toxicity

  • 1.

    H ypersensitivity reaction with skin rashes; itching, urticaria, etc.

  • 2.

    H yperglycaemia: Due to insulin deficiency

  • 3.

    H eadache, H allucinations, confusion and coma

  • 4.

    H aemorrhage: Due to inhibition of synthesis of clotting factors

  • 5.

    Pancreatitis

Miscellaneous agents

Hydroxyurea.

Hydroxyurea acts in the S phase of cell cycle (CCS drug).

Mechanism of action.

Hydroxyurea interferes with the conversion of ribonucleotide to deoxyribonucleotide by inhibiting ribonucleoside diphosphate reductase. This results in inhibition of DNA synthesis. It is used mainly in CML, polycythaemia vera and psoriasis. The common side effects are bone marrow suppression with leucopenia, anaemia and thrombocytopenia.

Other anticancer drugs are shown in Table 11.29 .

Table 11.29 ■
Targeted drugs for cancer
Drug Use Adverse effects
  • Tyrosine kinase inhibitor

  • Imatinib: (–) Tyr kinase of chronic myeloid leukaemia (CML) cells

  • CML

  • Vomiting, abdominal pain

  • Angiogenesis inhibitor

  • Bevacizumab (vascular endothelium growth factor inhibitor): binds to VEGF and blocks its binding to receptor

  • Sorafenib (VEGF inhibitor)

  • Renal cell cancer

  • Lung cancer

  • Breast cancer


Hepatocellular carcinoma
  • Hypertension, thromboembolism, bleeding


Anorexia, hypertension
  • Epidermal growth factor receptor inhibitor

  • Gefitinib: (-) cellular growth and proloiferation

  • Non-small cell lung cancer

  • Rash, diarrhoea

Proteasome inhibitor
Bortezomib: Binds proteasome

(−) proteolytic activity

(−) cell proliferation
(+) apoptosis
Multiple myeloma Peripheral neuropathy
Monoclonal antibodies
Rituximab: Binds to antigen on surface of B lymphocytes and B cell lymphoma
B cell lymphoma Infusion reaction
CML, chronic myeloid leukaemia.

Hormones and hormone antagonists

  • 1.

    Glucocorticoids: Because of their marked lympholytic action, they are used in acute leukaemias and lymphomas. Apart from this effect, glucocorticoids:

    • (a)

      Have anti-inflammatory effect, decrease oedema associated with the tumour

    • (b)

      Produce feeling of well-being

    • (c)

      Suppress hypersensitivity reaction due to certain anticancer drugs

    • (d)

      Control hypercalcaemia

    • (e)

      Increase the antiemetic effect of ondansetron/granisetron/metoclopramide

      • Because of the above effects, glucocorticoids are useful in the treatment of various cancers.

  • 2.

    Oestrogens: The oestrogens are physiological antagonists of androgens. Hence, they are used to antagonize the effects of androgens in androgen-dependent prostatic tumours. Fosfestrol is a prodrug which is activated to stilboestrol in prostatic tissue. It achieves high concentration in prostatic tissue, therefore is preferred in carcinoma of prostate.

  • 3.

    Tamoxifen: This is an antioestrogen mainly used in the palliative treatment of hormone-dependent breast carcinoma.

  • 4.

    Progestins: The progestins are useful in endometrial carcinoma.

  • 5.

    Antiandrogens: Flutamide is a nonsteroidal agent that blocks the action of androgen at the receptor level.

  • 6.

    Finasteride: This blocks the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase.

    • Both flutamide and finasteride are useful for the palliative treatment of advanced carcinoma of prostate. Finasteride is also effective in BPH.

  • 7.

    Aromatase inhibitors: They are used in hormone-dependent breast cancer in postmenopausal women.

  • 8.

    GnRH agonists: The pulsatile administration of these agents (buserelin, goserelin, leuprolide, etc.) produces a rise in follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Continuous administration, however, suppresses the pituitary gonadotropins by downregulating GnRH receptors. These agents produce palliative effects in advanced prostatic and breast cancers.